32. Richardson, T.I.; Norman, B.H.; Lugar, C.W.; Jones, S.A.; Wang, Y.; Durbin, J.D.; Krishnan, V.; Dodge, J.A. Benzopyrans as selective estrogen receptor β agonists (SERBAs). Part 2: Structure-activity relationship studies on the benzopyran scaffold. *Bioorg. Med. Chem. Lett.* **2007**, *17*, 3570–3574. [CrossRef] [PubMed]

33. Richardson, T.I.; Dodge, J.A.; Durst, G.L.; Pfeifer, L.A.; Shah, J.; Wang, Y.; Durbin, J.D.; Krishnan, V.; Norman, B.H. Benzopyrans as selective estrogen receptor β agonists (SERBAs). Part 3: Synthesis of cyclopentanone and cyclohexanone intermediates for C-ring modification. *Bioorg. Med. Chem. Lett.* **2007**, *17*, 4824–4828. [CrossRef] [PubMed]

34. Vajdos, F.F.; Hoth, L.R.; Geoghegan, K.F.; Simons, S.P.; LeMotte, P.K.; Danley, D.E.; Ammirati, M.J.; Pandit, J. The 2.0 Å crystal structure of the ERα ligand-binding domain complexed with lasofoxifene. *Protein Sci.* **2007**, *16*, 897–905. [CrossRef] [PubMed]

35. Hummel, C.W.; Geiser, A.G.; Bryant, H.U.; Cohen, I.R.; Dally, R.D.; Fong, K.C.; Frank, S.A.; Hinklin, R.; Jones, S.A.; Lewis, G. A selective estrogen receptor modulator designed for the treatment of uterine leiomyoma with unique tissue specificity for uterus and ovaries in rats. *J. Med. Chem.* **2005**, *48*, 6772–6775. [CrossRef]

36. Renaud, J.; Bischoff, S.F.; Buhl, T.; Floersheim, P.; Fournier, B.; Geiser, M.; Halleux, C.; Kallen, J.; Keller, H.; Ramage, P. Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERα-selective tetrahydroisoquinoline ligands. *J. Med. Chem.* **2005**, *48*, 364–379. [CrossRef]

37. Blizzard, T.A.; DiNinno, F.; Morgan, J.D.; Chen, H.Y.; Wu, J.Y.; Kim, S.; Chan, W.; Birzin, E.T.; Yang, Y.T.; Pai, L.-Y. Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers. *Bioorg. Med. Chem. Lett.* **2005**, *15*, 107–113. [CrossRef]

38. Wu, Y.-L.; Yang, X.; Ren, Z.; McDonnell, D.P.; Norris, J.D.; Willson, T.M.; Greene, G.L. Structural basis for an unexpected mode of SERM-mediated ER antagonism. *Mol. Cell* **2005**, *18*, 413–424. [CrossRef]

39. Kim, S.; Wu, J.Y.; Birzin, E.T.; Frisch, K.; Chan, W.; Pai, L.-Y.; Yang, Y.T.; Mosley, R.T.; Fitzgerald, P.M.; Sharma, N. Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor α modulators. *J. Med. Chem.* **2004**, *47*, 2171–2175. [CrossRef]

40. Leduc, A.-M.; Trent, J.O.; Wittliff, J.L.; Bramlett, K.S.; Briggs, S.L.; Chirgadze, N.Y.; Wang, Y.; Burris, T.P.; Spatola, A.F. Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. *Proc. Natl. Acad. Sci. USA* **2003**, *100*, 11273–11278. [CrossRef]

41. Renaud, J.; Bischoff, S.F.; Buhl, T.; Floersheim, P.; Fournier, B.; Halleux, C.; Kallen, J.; Keller, H.; Schlaeppi, J.-M.; Stark, W. Estrogen receptor modulators: Identification and structure-activity relationships of potent ERα-selective tetrahydroisoquinoline ligands. *J. Med. Chem.* **2003**, *46*, 2945–2957. [CrossRef]

42. Wärnmark, A.; Treuter, E.; Gustafsson, J.-Å.; Hubbard, R.E.; Brzozowski, A.M.; Pike, A.C. Interaction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor α. *J. Biol. Chem.* **2002**, *277*, 21862–21868. [CrossRef] [PubMed]

43. Gangloff, M.; Ruff, M.; Eiler, S.; Duclaud, S.; Wurtz, J.M.; Moras, D. Crystal structure of a mutant hERα ligand-binding domain reveals key structural features for the mechanism of partial agonism. *J. Biol. Chem.* **2001**, *276*, 15059–15065. [CrossRef] [PubMed]

44. Shiau, A.K.; Barstad, D.; Loria, P.M.; Cheng, L.; Kushner, P.J.; Agard, D.A.; Greene, G.L. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. *Cell* **1998**, *95*, 927–937. [CrossRef]

45. Tanenbaum, D.M.; Wang, Y.; Williams, S.P.; Sigler, P.B. Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains. *Proc. Natl. Acad. Sci. USA* **1998**, *95*, 5998–6003. [CrossRef]

46. Brzozowski, A.M.; Pike, A.C.; Dauter, Z.; Hubbard, R.E.; Bonn, T.; Engström, O.; Öhman, L.; Greene, G.L.; Gustafsson, J.-Å.; Carlquist, M. Molecular basis of agonism and antagonism in the oestrogen receptor. *Nature* **1997**, *389*, 753–758. [CrossRef] [PubMed]

47. Burslem, G.M.; Crews, C.M. Small-molecule modulation of protein homeostasis. *Chem. Rev.* **2017**, *117*, 11269–11301. [CrossRef] [PubMed]

48. Ottis, P.; Crews, C.M. Proteolysis-targeting chimeras: Induced protein degradation as a therapeutic strategy. *ACS Chem. Biol.* **2017**, *12*, 892–898. [CrossRef]

49. Negi, A.; Voisin-Chiret, A.S. Strategies to Reduce the On-Target Platelet Toxicity of Bcl-xL Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches. *ChemBioChem* **2022**, *23*, e202100689. [CrossRef]

50. Ma, Z.; Ji, Y.; Yu, Y.; Liang, D. Specific non-genetic IAP-based protein erasers (SNIPERs) as a potential therapeutic strategy. *Eur. J. Med. Chem.* **2021**, *216*, 113247. [CrossRef]

51. Zhong, Y.; Chi, F.; Wu, H.; Liu, Y.; Xie, Z.; Huang, W.; Shi, W.; Qian, H. Emerging targeted protein degradation tools for innovative drug discovery: From classical PROTACs to the novel and beyond. *Eur. J. Med. Chem.* **2022**, *231*, 114142. [CrossRef]

52. Wang, C.; Zhang, Y.; Wang, J.; Xing, D. VHL-based PROTACs as potential therapeutic agents: Recent progress and perspectives. *Eur. J. Med. Chem.* **2022**, *227*, 113906. [CrossRef] [PubMed]

53. Negi, A.; Murphy, P.V. Development of Mcl-1 inhibitors for cancer therapy. *Eur. J. Med. Chem.* **2021**, *210*, 113038. [CrossRef] [PubMed]

54. Lin, X.; Xiang, H.; Luo, G. Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance. *Eur. J. Med. Chem.* **2020**, *206*, 112689. [CrossRef] [PubMed]

55. Culig, Z.; Klocker, H.; Bartsch, G.; Steiner, H.; Hobisch, A. Androgen receptors in prostate cancer. *J. Urol.* **2003**, *170*, 1363–1369. [CrossRef] [PubMed]

56. Parkin, D.M.; Bray, F.; Ferlay, J.; Pisani, P. Global cancer statistics. *CA A Cancer J. Clin.* **2005**, *55*, 74–108. [CrossRef]
32. Richardson, T.I.; Norman, B.H.; Lugar, C.W.; Jones, S.A.; Wang, Y.; Durbin, J.D.; Krishnan, V.; Dodge, J.A. Benzopyrans as selective estrogen receptor β agonists (SERBAs). Part 2: Structure-activity relationship studies on the benzopyran scaffold. *Bioorg. Med. Chem. Lett.* **2007**, *17*, 3570–3574. [CrossRef] [PubMed]

33. Richardson, T.I.; Dodge, J.A.; Durst, G.L.; Pfeifer, L.A.; Shah, J.; Wang, Y.; Durbin, J.D.; Krishnan, V.; Norman, B.H. Benzopyrans as selective estrogen receptor β agonists (SERBAs). Part 3: Synthesis of cyclopentanone and cyclohexanone intermediates for C-ring modification. *Bioorg. Med. Chem. Lett.* **2007**, *17*, 4824–4828. [CrossRef] [PubMed]

34. Vajdos, F.F.; Hoth, L.R.; Geoghegan, K.F.; Simons, S.P.; LeMotte, P.K.; Danley, D.E.; Ammirati, M.J.; Pandit, J. The 2.0 Å crystal structure of the ERα ligand-binding domain complexed with lasofoxifene. *Protein Sci.* **2007**, *16*, 897–905. [CrossRef] [PubMed]

35. Hummel, C.W.; Geiser, A.G.; Bryant, H.U.; Cohen, I.R.; Dally, R.D.; Fong, K.C.; Frank, S.A.; Hinklin, R.; Jones, S.A.; Lewis, G. A selective estrogen receptor modulator designed for the treatment of uterine leiomyoma with unique tissue specificity for uterus and ovaries in rats. *J. Med. Chem.* **2005**, *48*, 6772–6775. [CrossRef]

36. Renaud, J.; Bischoff, S.F.; Buhl, T.; Floersheim, P.; Fournier, B.; Geiser, M.; Halleux, C.; Kallen, J.; Keller, H.; Ramage, P. Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERα-selective tetrahydroisoquinoline ligands. *J. Med. Chem.* **2005**, *48*, 364–379. [CrossRef]

37. Blizzard, T.A.; DiNinno, F.; Morgan, J.D.; Chen, H.Y.; Wu, J.Y.; Kim, S.; Chan, W.; Birzin, E.T.; Yang, Y.T.; Pai, L.-Y. Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers. *Bioorg. Med. Chem. Lett.* **2005**, *15*, 107–113. [CrossRef]

38. Wu, Y.-L.; Yang, X.; Ren, Z.; McDonnell, D.P.; Norris, J.D.; Willson, T.M.; Greene, G.L. Structural basis for an unexpected mode of SERM-mediated ER antagonism. *Mol. Cell* **2005**, *18*, 413–424. [CrossRef]

39. Kim, S.; Wu, J.Y.; Birzin, E.T.; Frisch, K.; Chan, W.; Pai, L.-Y.; Yang, Y.T.; Mosley, R.T.; Fitzgerald, P.M.; Sharma, N. Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor α modulators. *J. Med. Chem.* **2004**, *47*, 2171–2175. [CrossRef]

40. Leduc, A.-M.; Trent, J.O.; Wittliff, J.L.; Bramlett, K.S.; Briggs, S.L.; Chirgadze, N.Y.; Wang, Y.; Burris, T.P.; Spatola, A.F. Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. *Proc. Natl. Acad. Sci. USA* **2003**, *100*, 11273–11278. [CrossRef]

41. Renaud, J.; Bischoff, S.F.; Buhl, T.; Floersheim, P.; Fournier, B.; Halleux, C.; Kallen, J.; Keller, H.; Schlaeppi, J.-M.; Stark, W. Estrogen receptor modulators: Identification and structure-activity relationships of potent ERα-selective tetrahydroisoquinoline ligands. *J. Med. Chem.* **2003**, *46*, 2945–2957. [CrossRef]

42. Wärnmark, A.; Treuter, E.; Gustafsson, J.-Å.; Hubbard, R.E.; Brzozowski, A.M.; Pike, A.C. Interaction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor α. *J. Biol. Chem.* **2002**, *277*, 21862–21868. [CrossRef] [PubMed]

43. Gangloff, M.; Ruff, M.; Eiler, S.; Duclaud, S.; Wurtz, J.M.; Moras, D. Crystal structure of a mutant hERα ligand-binding domain reveals key structural features for the mechanism of partial agonism. *J. Biol. Chem.* **2001**, *276*, 15059–15065. [CrossRef] [PubMed]

44. Shiau, A.K.; Barstad, D.; Loria, P.M.; Cheng, L.; Kushner, P.J.; Agard, D.A.; Greene, G.L. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. *Cell* **1998**, *95*, 927–937. [CrossRef]

45. Tanenbaum, D.M.; Wang, Y.; Williams, S.P.; Sigler, P.B. Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains. *Proc. Natl. Acad. Sci. USA* **1998**, *95*, 5998–6003. [CrossRef]

46. Brzozowski, A.M.; Pike, A.C.; Dauter, Z.; Hubbard, R.E.; Bonn, T.; Engström, O.; Öhman, L.; Greene, G.L.; Gustafsson, J.-Å.; Carlquist, M. Molecular basis of agonism and antagonism in the oestrogen receptor. *Nature* **1997**, *389*, 753–758. [CrossRef] [PubMed]

47. Burslem, G.M.; Crews, C.M. Small-molecule modulation of protein homeostasis. *Chem. Rev.* **2017**, *117*, 11269–11301. [CrossRef] [PubMed]

48. Ottis, P.; Crews, C.M. Proteolysis-targeting chimeras: Induced protein degradation as a therapeutic strategy. *ACS Chem. Biol.* **2017**, *12*, 892–898. [CrossRef]

49. Negi, A.; Voisin-Chiret, A.S. Strategies to Reduce the On-Target Platelet Toxicity of Bcl-xL Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches. *ChemBioChem* **2022**, *23*, e202100689. [CrossRef]

50. Ma, Z.; Ji, Y.; Yu, Y.; Liang, D. Specific non-genetic IAP-based protein erasers (SNIPERs) as a potential therapeutic strategy. *Eur. J. Med. Chem.* **2021**, *216*, 113247. [CrossRef]

51. Zhong, Y.; Chi, F.; Wu, H.; Liu, Y.; Xie, Z.; Huang, W.; Shi, W.; Qian, H. Emerging targeted protein degradation tools for innovative drug discovery: From classical PROTACs to the novel and beyond. *Eur. J. Med. Chem.* **2022**, *231*, 114142. [CrossRef]

52. Wang, C.; Zhang, Y.; Wang, J.; Xing, D. VHL-based PROTACs as potential therapeutic agents: Recent progress and perspectives. *Eur. J. Med. Chem.* **2022**, *227*, 113906. [CrossRef] [PubMed]

53. Negi, A.; Murphy, P.V. Development of Mcl-1 inhibitors for cancer therapy. *Eur. J. Med. Chem.* **2021**, *210*, 113038. [CrossRef] [PubMed]

54. Lin, X.; Xiang, H.; Luo, G. Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance. *Eur. J. Med. Chem.* **2020**, *206*, 112689. [CrossRef] [PubMed]

55. Culig, Z.; Klocker, H.; Bartsch, G.; Steiner, H.; Hobisch, A. Androgen receptors in prostate cancer. *J. Urol.* **2003**, *170*, 1363–1369. [CrossRef] [PubMed]

56. Parkin, D.M.; Bray, F.; Ferlay, J.; Pisani, P. Global cancer statistics. *CA A Cancer J. Clin.* **2005**, *55*, 74–108. [CrossRef]
57. Huggins, C. Endocrine-induced regression of cancers. *Science* **1967**, *156*, 1050–1054. [CrossRef]

58. Ellis, M.J.; Coop, A.; Singh, B.; Mauriac, L.; Llombert-Cussac, A.; Jänicke, F.; Miller, W.R.; Evans, D.B.; Dugan, M.; Brady, C. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1-and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. *J. Clin. Oncol.* **2001**, *19*, 3808–3816. [CrossRef]

59. Buzdar, A.U. Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer. *Oncol. 2003*, **8**, 335–341. [CrossRef]

60. Clarke, R.; Skaar, T.; Leonessa, F.; Brankin, B.; James, M.; Brünner, N.; Lippman, M.E. Acquisition of an antiestrogen-resistant phenotype in breast cancer: Role of cellular and molecular mechanisms. *Drug Resist. 1996*, *87*, 263–283.

61. Santen, R.J. Endocrine treatment of prostate cancer. *Endocrinologist* **1992**, *2*, 384–392. [CrossRef]

62. Savarese, D.; Halabi, S.; Hars, V.; Akerley, W.; Taplin, M.; Godley, P.; Hussain, A.; Small, E.; Vogelzang, N. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: A final report of CALGB. *J. Clin. Oncol.* **2001**, *19*, 2509–2516. [CrossRef] [PubMed]

63. Culig, Z.; Hobisch, A.; Cronauer, M.V.; Radmayr, C.; Trapman, J.; Hittmair, A.; Bartsch, G.; Klocker, H. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. *Cancer Res.* **1994**, *54*, 5474–5478. [CrossRef] [PubMed]

64. Gaddipati, J.P.; McLeod, D.G.; Heidenberg, H.B.; Sesterhenn, I.A.; Finger, M.J.; Moul, J.W.; Srivastava, S. Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. *Cancer Res.* **1994**, *54*, 2861–2864. [PubMed]

65. Bubendorf, L.; Kononen, J.; Koivisto, P.; Schraml, P.; Moch, H.; Gasser, T.C.; Willi, N.; Mihatsch, M.J.; Sauter, G.; Kallioniemi, O.-P. Survey of gene amplifications during prostate cancer progression by high-throughput fluorescence in situ hybridization on tissue microarrays. *Cancer Res.* **1999**, *59*, 803–806.

66. Craft, N.; Shostak, Y.; Carey, M.; Sawyers, C.L. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. *Nat. Med.* **1999**, *5*, 280–285. [CrossRef]

67. Taplin, M.-E.; Bubley, G.J.; Ko, Y.-J.; Small, E.J.; Upton, M.; Rajeshkumar, B.; Balk, S.P. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. *Cancer Res.* **1999**, *59*, 2511–2515.

68. Godoy-Tundidor, S.; Hobisch, A.; Pfeil, K.; Bartsch, G.; Culig, Z. Acquisition of agonistic properties of nonsteroidal antiandrogens after treatment with oncostatin M in prostate cancer cells. *Clin. Cancer Res.* **2002**, *8*, 2356–2361.

69. Ueda, T.; Bruchovsky, N.; Sadar, M.D. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. *J. Biol. Chem.* **2002**, *277*, 7076–7085. [CrossRef]

70. Bakin, R.E.; Gioeli, D.; Sikes, R.A.; Bissonette, E.A.; Weber, M.J. Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. *Cancer Res.* **2003**, *63*, 1981–1989.

71. Franco, O.E.; Onishi, T.; Yamakawa, K.; Arima, K.; Yanagawa, M.; Sugimura, Y.; Kawamura, J. Mitogen-activated protein kinase pathway is involved in androgen-independent PSA gene expression in LNCaP cells. *Prostate* **2003**, *56*, 319–325. [CrossRef]

72. Sakamoto, K.M.; Kim, K.B.; Verma, R.; Ransick, A.; Stein, B.; Crews, C.M.; Deshaies, R.J. Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. *Mol. Cell. Proteom.* **2003**, *2*, 1350–1358. [CrossRef] [PubMed]

73. Verma, R.; Chen, S.; Feldman, R.; Schieltz, D.; Yates, J.; Dohmen, J.; Deshaies, R.J. Proteasomal proteomics: Identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. *Mol. Biol. Cell* **2000**, *11*, 3425–3439. [CrossRef] [PubMed]

74. Karin, M.; Ben-Neriah, Y. Phosphorylation meets ubiquitination: The control of NF-(kappa) B activity. *Annu. Rev. Immunol.* **2000**, *18*, 621. [CrossRef] [PubMed]

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79. Ivan, M.; Kondo, K.; Yang, H.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J.M.; Lane, W.S.; Kaelin, W.G., Jr. HIFα targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. *Science* **2001**, *292*, 464–468. [CrossRef]

80. Jaakkola, P.; Mole, D.R.; Tian, Y.-M.; Wilson, M.I.; Gielbert, J.; Gaskell, S.J.; Kriegsheim, A.v.; Hebestreit, H.F.; Mukherji, M.; Schofield, C.J. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. *Science* **2001**, *292*, 468–472. [CrossRef]

81. Cyrus, K.; Wehenkel, M.; Choi, E.Y.; Lee, H.; Swanson, H.; Kim, K.B. Jostling for Position: Optimizing Linker Location in the Design of Estrogen Receptor-Targeting PROTACs. *ChemMedChem* **2010**, *5*, 979–985. [CrossRef]

82. Kuduk, S.D.; Harris, C.R.; Zheng, F.F.; Sepp-Lorenzino, L.; Ouerfelli, Q.; Rosen, N.; Danishefsky, S.J. Synthesis and evaluation of geldanamycin-testosterone hybrids. *Bioorg. Med. Chem. Lett.* **2000**, *10*, 1303–1306. [CrossRef]

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84. Wakeling, A.E. Regulatory mechanisms in breast cancer. Steroidal pure antiestrogens. *Cancer Treat. Res.* **1991**, *53*, 239–257.
57. Huggins, C. Endocrine-induced regression of cancers. *Science* **1967**, *156*, 1050–1054. [CrossRef]

58. Ellis, M.J.; Coop, A.; Singh, B.; Mauriac, L.; Llombert-Cussac, A.; Jänicke, F.; Miller, W.R.; Evans, D.B.; Dugan, M.; Brady, C. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1-and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. *J. Clin. Oncol.* **2001**, *19*, 3808–3816. [CrossRef]

59. Buzdar, A.U. Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer. *Oncol. 2003*, *8*, 335–341. [CrossRef]

60. Clarke, R.; Skaar, T.; Leonessa, F.; Brankin, B.; James, M.; Brünner, N.; Lippman, M.E. Acquisition of an antiestrogen-resistant phenotype in breast cancer: Role of cellular and molecular mechanisms. *Drug Resist. 1996*, *87*, 263–283.

61. Santen, R.J. Endocrine treatment of prostate cancer. *Endocrinologist* **1992**, *2*, 384–392. [CrossRef]

62. Savarese, D.; Halabi, S.; Hars, V.; Akerley, W.; Taplin, M.; Godley, P.; Hussain, A.; Small, E.; Vogelzang, N. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: A final report of CALGB. *J. Clin. Oncol.* **2001**, *19*, 2509–2516. [CrossRef] [PubMed]

63. Culig, Z.; Hobisch, A.; Cronauer, M.V.; Radmayr, C.; Trapman, J.; Hittmair, A.; Bartsch, G.; Klocker, H. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. *Cancer Res.* **1994**, *54*, 5474–5478. [CrossRef] [PubMed]

64. Gaddipati, J.P.; McLeod, D.G.; Heidenberg, H.B.; Sesterhenn, I.A.; Finger, M.J.; Moul, J.W.; Srivastava, S. Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. *Cancer Res.* **1994**, *54*, 2861–2864. [PubMed]

65. Bubendorf, L.; Kononen, J.; Koivisto, P.; Schraml, P.; Moch, H.; Gasser, T.C.; Willi, N.; Mihatsch, M.J.; Sauter, G.; Kallioniemi, O.-P. Survey of gene amplifications during prostate cancer progression by high-throughput fluorescence in situ hybridization on tissue microarrays. *Cancer Res.* **1999**, *59*, 803–806.

66. Craft, N.; Shostak, Y.; Carey, M.; Sawyers, C.L. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. *Nat. Med.* **1999**, *5*, 280–285. [CrossRef]

67. Taplin, M.-E.; Bubley, G.J.; Ko, Y.-J.; Small, E.J.; Upton, M.; Rajeshkumar, B.; Balk, S.P. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. *Cancer Res.* **1999**, *59*, 2511–2515.

68. Godoy-Tundidor, S.; Hobisch, A.; Pfeil, K.; Bartsch, G.; Culig, Z. Acquisition of agonistic properties of nonsteroidal antiandrogens after treatment with oncostatin M in prostate cancer cells. *Clin. Cancer Res.* **2002**, *8*, 2356–2361.

69. Ueda, T.; Bruchovsky, N.; Sadar, M.D. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. *J. Biol. Chem.* **2002**, *277*, 7076–7085. [CrossRef]

70. Bakin, R.E.; Gioeli, D.; Sikes, R.A.; Bissonette, E.A.; Weber, M.J. Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. *Cancer Res.* **2003**, *63*, 1981–1989.

71. Franco, O.E.; Onishi, T.; Yamakawa, K.; Arima, K.; Yanagawa, M.; Sugimura, Y.; Kawamura, J. Mitogen-activated protein kinase pathway is involved in androgen-independent PSA gene expression in LNCaP cells. *Prostate* **2003**, *56*, 319–325. [CrossRef]

72. Sakamoto, K.M.; Kim, K.B.; Verma, R.; Ransick, A.; Stein, B.; Crews, C.M.; Deshaies, R.J. Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. *Mol. Cell. Proteom.* **2003**, *2*, 1350–1358. [CrossRef] [PubMed]

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177. Bondeson, D.P.; Mares, A.; Smith, I.E.; Ko, E.; Campos, S.; Miah, A.H.; Mulholland, K.E.; Routly, N.; Buckley, D.L.; Gustafson, J.L. Catalytic in vivo protein knockdown by small-molecule PROTACs. *Nat. Chem. Biol.* **2015**, *11*, 611–617. [CrossRef] [PubMed]

178. Ranhotra, H.S. The estrogen-related receptor alpha: The oldest, yet an energetic orphan with robust biological functions. *J. Recept. Signal Transduct.* **2010**, *30*, 193–205. [CrossRef] [PubMed]

179. Schmidt, R.; Geissler, D.; Hagen, V.; Bendig, J. Mechanism of photocleavage of (coumarin-4-yl) methyl esters. *J. Phys. Chem. A* **2007**, *111*, 5768–5774. [CrossRef]
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183. Zhou, J.; Negi, A.; Mirallai, S.I.; Warta, R.; Herold-Mende, C.; Carty, M.P.; Ye, X.-S.; Murphy, P.V. N-Alkyl-1, 5-dideoxy-1, 5-imino-L-fucitols as fucosidase inhibitors: Synthesis, molecular modelling and activity against cancer cell lines. *Bioorg. Chem.* **2019**, *84*, 418–433. [CrossRef]

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187. Cecchini, C.; Pannilunghi, S.; Tardy, S.; Scapozza, L. From conception to development: Investigating PROTACs features for improved cell permeability and successful protein degradation. *Front. Chem.* **2021**, *9*, 672267. [CrossRef] [PubMed]

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191. Joshi, G.; Singh, P.K.; Negi, A.; Rana, A.; Singh, S.; Kumar, R. Growth factors mediated cell signalling in prostate cancer progression: Implications in discovery of anti-prostate cancer agents. *Chem. Biol. Interac.* **2015**, *24*, 120–133. [CrossRef]

192. Hevener, K.E. Computational toxicology methods in chemical library design and high-throughput screening hit validation. *Comput. Toxicol* **2018**, *1800*, 275–285.

193. Goya-Jorge, E.; Doan, T.; Scippo, M.-L.; Muller, M.; Giner, R.; Barigye, S.J.; Gozalbes, R. Elucidating the aryl hydrocarbon receptor antagonism from a chemical-structural perspective. *SAR QSAR Environ. Res.* **2020**, *31*, 209–226. [CrossRef]

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195. Negi, A.; Alex, J.M.; Amrutkar, S.M.; Baviskar, A.T.; Joshi, G.; Singh, S.; Banerjee, U.C.; Kumar, R. Imine/amide-imidazole conjugates derived from 5-amino-4-cyano-N1-substituted benzyl imidazole: Microwave-assisted synthesis and anticancer activity via selective topoisomerase-II-α inhibition. *Bioorg. Med. Chem.* **2015**, *23*, 5654–5661. [CrossRef]

196. Strittmatter, S.M. Overcoming drug development bottlenecks with repurposing: Old drugs learn new tricks. *Nat. Med.* **2014**, *20*, 590–591. [CrossRef]

197. Rastelli, G.; Pellati, F.; Pinzi, L.; Gamberini, M.C. Repositioning natural products in drug discovery. *Molecules* **2020**, *25*, 1154. [CrossRef]

198. Negi, A.; Bhandari, N.; Shyamlal, B.R.K.; Chaudhary, S. Inverse docking based screening and identification of protein targets for Cassiarin alkaloids against Plasmodium falciparum. *Saudi Pharm. J.* **2018**, *26*, 546–567. [CrossRef] [PubMed]

199. Thomford, N.E.; Senthebane, D.A.; Rowe, A.; Munro, D.; Seele, P.; Maroyi, A.; Dzobo, K. Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. *Int. J. Mol. Sci.* **2018**, *19*, 1578. [CrossRef] [PubMed]

200. Gollapudi, R.; Gallagher, R.J.; Negi, A.; Motohashi, N. The phytochemicals and health benefits of murraya koenigii. In *Occurrences, Structure, Biosynthesis, and Health Benefits Based on Their Evidences of Medicinal Phytochemicals in Vegetables and Fruits*; Motohashi, N., Ed.; Nova Science Publishers, Inc.: Hauppauge, NY, USA, 2017; pp. 113–182.

201. Negi, A.; Murphy, P.V. Natural products as Mcl-1 inhibitors: A comparative study of experimental and computational modelling data. *Chemistry* **2022**, *4*, 983–1009. [CrossRef]

202. Joubert, N.; Denevault-Sabourin, C.; Bryden, F.; Viaud-Massuard, M.-C. Towards antibody-drug conjugates and prodrug strategies with extracellular stimuli-responsive drug delivery in the tumor microenvironment for cancer therapy. *Eur. J. Med. Chem.* **2017**, *142*, 393–415. [CrossRef]

203. Negi, A.; Kesari, K.K. Chitosan Nanoparticle Encapsulation of Antibacterial Essential Oils. *Micromachines* **2022**, *13*, 1265. [CrossRef]

204. Bellmann, L.; Klein, R.; Rarey, M. Calculating and Optimizing Physicochemical Property Distributions of Large Combinatorial Fragment Spaces. *J. Chem. Inf. Model.* **2022**, *62*, 2800–2810. [CrossRef]
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181. Negi, A.; Zhou, J.; Sweeney, S.; Murphy, P.V. Ligand design for somatostatin receptor isoforms 4 and 5. *Eur. J. Med. Chem.* **2019**, *163*, 148–159. [CrossRef]

182. McHugh, M.A. Ligand-Gated Ion Channels: Putative Target Sites for Anthelmintic Therapy in Muscle and Intestine Cells of Parasitic Nematodes. Ph.D. Thesis, Iowa State University, Ames, IA, USA, 2021.

183. Zhou, J.; Negi, A.; Mirallai, S.I.; Warta, R.; Herold-Mende, C.; Carty, M.P.; Ye, X.-S.; Murphy, P.V. N-Alkyl-1, 5-dideoxy-1, 5-imino-L-fucitols as fucosidase inhibitors: Synthesis, molecular modelling and activity against cancer cell lines. *Bioorg. Chem.* **2019**, *84*, 418–433. [CrossRef]

184. Olanders, G.; Brandt, P.; Sköld, C.; Karlén, A. Computational studies of molecular pre-organization through macrocyclization: Conformational distribution analysis of closely related non-macrocyclic and macrocyclic analogs. *Bioorg. Med. Chem.* **2021**, *49*, 116399. [CrossRef]

185. Raynal, L.; Rose, N.C.; Donald, J.R.; Spicer, C.D. Photochemical Methods for Peptide Macrocyclisation. *Chem. Eur. J.* **2021**, *27*, 69. [CrossRef]

186. Attwood, M.M.; Fabbro, D.; Sokolov, A.V.; Knapp, S.; Schiöth, H.B. Trends in kinase drug discovery: Targets, indications and inhibitor design. *Nat. Rev. Drug Discov.* **2021**, *20*, 1–23. [CrossRef]

187. Cecchini, C.; Pannilunghi, S.; Tardy, S.; Scapozza, L. From conception to development: Investigating PROTACs features for improved cell permeability and successful protein degradation. *Front. Chem.* **2021**, *9*, 672267. [CrossRef] [PubMed]

188. Zhou, J.; Reidy, M.; O'Reilly, C.; Jarikote, D.V.; Negi, A.; Samali, A.; Szegezdi, E.; Murphy, P.V. Decorated macrocycles via ring-closing double-reductive amination. Identification of an apoptosis inducer of leukemic cells that at least partially antagonizes a 5-HT2 receptor. *Org. Lett.* **2015**, *17*, 1672–1675. [CrossRef] [PubMed]

189. Negi, A.; Reilly, C.O.; Jarikote, D.V.; Zhou, J.; Murphy, P.V. Multi-targeting protein-protein interaction inhibitors: Evolution of macrocyclic ligands with embedded carbohydrates (MECs) to improve selectivity. *Eur. J. Med. Chem.* **2019**, *176*, 292–309. [CrossRef] [PubMed]

190. Nahta, R.; Yuan, L.X.; Zhang, B.; Kobayashi, R.; Esteva, F.J. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. *Cancer Res.* **2005**, *65*, 11118–11128. [CrossRef]

191. Joshi, G.; Singh, P.K.; Negi, A.; Rana, A.; Singh, S.; Kumar, R. Growth factors mediated cell signalling in prostate cancer progression: Implications in discovery of anti-prostate cancer agents. *Chem. Biol. Interac.* **2015**, *24*, 120–133. [CrossRef]

192. Hevener, K.E. Computational toxicology methods in chemical library design and high-throughput screening hit validation. *Comput. Toxicol* **2018**, *1800*, 275–285.

193. Goya-Jorge, E.; Doan, T.; Scippo, M.-L.; Muller, M.; Giner, R.; Barigye, S.J.; Gozalbes, R. Elucidating the aryl hydrocarbon receptor antagonism from a chemical-structural perspective. *SAR QSAR Environ. Res.* **2020**, *31*, 209–226. [CrossRef]

194. Singh, P.K.; Negi, A.; Gupta, P.K.; Chauhan, M.; Kumar, R. Toxicophore exploration as a screening technology for drug design and discovery: Techniques, scope and limitations. *Arch. Toxicol* **2016**, *90*, 1785–1802. [CrossRef]

195. Negi, A.; Alex, J.M.; Amrutkar, S.M.; Baviskar, A.T.; Joshi, G.; Singh, S.; Banerjee, U.C.; Kumar, R. Imine/amide-imidazole conjugates derived from 5-amino-4-cyano-N1-substituted benzyl imidazole: Microwave-assisted synthesis and anticancer activity via selective topoisomerase-II-α inhibition. *Bioorg. Med. Chem.* **2015**, *23*, 5654–5661. [CrossRef]

196. Strittmatter, S.M. Overcoming drug development bottlenecks with repurposing: Old drugs learn new tricks. *Nat. Med.* **2014**, *20*, 590–591. [CrossRef]

197. Rastelli, G.; Pellati, F.; Pinzi, L.; Gamberini, M.C. Repositioning natural products in drug discovery. *Molecules* **2020**, *25*, 1154. [CrossRef]

198. Negi, A.; Bhandari, N.; Shyamlal, B.R.K.; Chaudhary, S. Inverse docking based screening and identification of protein targets for Cassiarin alkaloids against Plasmodium falciparum. *Saudi Pharm. J.* **2018**, *26*, 546–567. [CrossRef] [PubMed]

199. Thomford, N.E.; Senthebane, D.A.; Rowe, A.; Munro, D.; Seele, P.; Maroyi, A.; Dzobo, K. Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. *Int. J. Mol. Sci.* **2018**, *19*, 1578. [CrossRef] [PubMed]

200. Gollapudi, R.; Gallagher, R.J.; Negi, A.; Motohashi, N. The phytochemicals and health benefits of murraya koenigii. In *Occurrences, Structure, Biosynthesis, and Health Benefits Based on Their Evidences of Medicinal Phytochemicals in Vegetables and Fruits*; Motohashi, N., Ed.; Nova Science Publishers, Inc.: Hauppauge, NY, USA, 2017; pp. 113–182.

201. Negi, A.; Murphy, P.V. Natural products as Mcl-1 inhibitors: A comparative study of experimental and computational modelling data. *Chemistry* **2022**, *4*, 983–1009. [CrossRef]

202. Joubert, N.; Denevault-Sabourin, C.; Bryden, F.; Viaud-Massuard, M.-C. Towards antibody-drug conjugates and prodrug strategies with extracellular stimuli-responsive drug delivery in the tumor microenvironment for cancer therapy. *Eur. J. Med. Chem.* **2017**, *142*, 393–415. [CrossRef]

203. Negi, A.; Kesari, K.K. Chitosan Nanoparticle Encapsulation of Antibacterial Essential Oils. *Micromachines* **2022**, *13*, 1265. [CrossRef]

204. Bellmann, L.; Klein, R.; Rarey, M. Calculating and Optimizing Physicochemical Property Distributions of Large Combinatorial Fragment Spaces. *J. Chem. Inf. Model.* **2022**, *62*, 2800–2810. [CrossRef]
205. Gui, W.; Kodadek, T. Applications and Limitations of Oxime-Linked "Split PROTACs". *ChemBioChem* **2022**, *23*, e202200275.
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206. Negi, A.; Mirallai, S.I.; Konda, S.; Murphy, P.V. An improved method for synthesis of non-symmetric triarylpyridines. *Tetrahedron* **2022**, *121*, 132930. [CrossRef]

207. Hamilton, E.P.; Schott, A.F.; Nanda, R.; Lu, H.; Keung, C.F.; Gedrich, R.; Parameswaran, J.; Han, H.S.; Hurvitz, S.A. ARV-471, an estrogen receptor (ER) PROTAC degrader, combined with palbociclib in advanced ER+/human epidermal growth factor receptor 2-negative (HER2-) breast cancer: Phase 1b cohort (part C) of a phase 1/2 study. *J. Clin. Oncol.* **2022**, *40*, TPS1120.
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206. Negi, A.; Mirallai, S.I.; Konda, S.; Murphy, P.V. An improved method for synthesis of non-symmetric triarylpyridines. *Tetrahedron* **2022**, *121*, 132930. [CrossRef]

207. Hamilton, E.P.; Schott, A.F.; Nanda, R.; Lu, H.; Keung, C.F.; Gedrich, R.; Parameswaran, J.; Han, H.S.; Hurvitz, S.A. ARV-471, an estrogen receptor (ER) PROTAC degrader, combined with palbociclib in advanced ER+/human epidermal growth factor receptor 2-negative (HER2-) breast cancer: Phase 1b cohort (part C) of a phase 1/2 study. *J. Clin. Oncol.* **2022**, *40*, TPS1120.