Abstract 2314: Preclinical development of a highly potent and selective dual inhibitor of CDK4/6 for the treatment of cancer
Authors: Bantie Laychiluh , Tadesse Solomon , Likisa Jimma , Yu Mingfeng , Noll Benjamin , Albrecht Hugo , Milne Robert , Wang Shudong 
Published: August 2018

Cyclin-dependent kinases 4 and 6 (CDK4/6) in concert with D-type cyclins, are vital drivers of the cell cycle. Activated CDK4/6-cyclin D complexes regulate cell proliferation, senescence and apoptosis via phosphorylation of proteins including Rb, FOXM1 and SMAD3. Deregulation of the CDK4/6-cyclin D-Rb-E2F pathway has been found in over 90% of human cancers, and amplification of genes coding for cyclin D1 (CCND1) and CDK4/6, or deletions of the locus encoding p16INK4a are the major mechanisms. For instance, CCDN1 amplification and cyclin D protein overexpression are seen in ~ 35% and ≥ 50% of breast cancer cases, respectively. Similarly, ≥ 40% of prostate cancers overexpress CDK6 while loss of p16INK4a occurs in ~ 80% of head and neck squamous cell carcinoma. Specific mutations or translocations in the genes encoding CDK4/6-cyclin D-Rb-E2F pathway are aberrantly activated in melanoma and mantle cell lymphoma. Therefore, CDK4/6 inhibition can be an effective treatment strategy for these cancers.

With our extensive medicinal chemistry, biochemical and cellular assays, in vivo pharmacokinetic, safety and efficacy studies, we have identified a highly potent dual inhibitor of CDK4/6, 3-14, that showed excellent selectivity over a panel of &gt;360 kinases. 3-14 is more potent anti-proliferative agent than palbociclib against a range of cancer cell lines including breast, ovarian, colon, prostate, pancreatic, lung and melanoma cancer cells. 3-14 arrested cells in G1 phase of the cell cycle, prevented colony formation and induced senescence in MCF7 breast cancer cells. 3-14 caused dose dependent inhibition of Rb phosphorylation at S780, S795 and S807/11 residues, and this was translated to the reduction in the levels of E2F regulated proteins such as cyclin E2, A2. Moreover, 3-14 possessed excellent pharmaceutical properties, and pharmacokinetics with high oral bioavailability in rodents. 3-14 (MTD = 250 mg/kg) is better tolerated than palbociclib (MTD = 150 mg/kg) in mice. In A2780 ovarian cancer xenograft, 3-14 (100 mg/kg p.o. daily) delayed tumor growth (i.e. T/C = 24.4 %) and increased animal life span (90%), and was more efficacious

compared to palbociclib (i.e. T/C = 38% and ILS = 73%). Both 3-14 and palbociclib didn't cause histopathological changes in the bone marrow, intestine, liver, heart and kidney except for the non-significant reduction in the neutrophils. Given its excellent efficacy and safety as well as pharmacokinetic profiles, 3-14 is warranted as a development candidate for further preclinical and clinical studies.

Citation Format: Laychiluh Bantie, Solomon Tadesse, Jimma Likisa, Mingfeng Yu, Benjamin Noll, Hugo Albrecht, Robert Milne, Shudong Wang. Preclinical development of a highly potent and selective dual inhibitor of CDK4/6 for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2314.