Abstract 1143: Evaluation of AU-18069, a novel small molecule CBP/p300 bromodomain inhibitor for the treatment of cancers
Authors: Abbineni Chandrasekhar , Thiyagarajan Saravanan , Senaiar Ramesh S , Mukherjee Subhendu , Jaleel Mahaboobi , Marappan Sivapriya , N R Raghavendra , Renukappa Girish Aggunda , B Aravind A , R Naveen Kumar , Reddy Venkata Siva , Babu Asha , Srinivas Akhila , Yadlapalli Prasad , Gore Suraj T , Hemasankar Pathange , Dey Mamon , S Samiulla D , Naik Chandranath D , Antony Thomas , Nellore Kavitha , Chelur Shekar , Daginakatte Girish , Myllymäki Mikko , Wohlfahrt Gerd , Ramachandra Murali , Samajdar Susanta 
Published: July 2021

Background: E1A binding protein (p300) and its paralog CREB binding protein (CBP or CREBBP) are ubiquitously expressed acetyl transferases (HAT) that also act as co-activators for number of transcription factors including HIF1a, BRCA-1, p53, c-Myc and androgen receptor (AR). Both CBP and p300 possess bromodomain (BRD) and a lysine acetyltransferase (KAT) domain. These two closely related epigenetic modulators are known to play oncogenic roles in a variety of cancers. Functional synthetic lethal screens have identified preferential killing in CBP-deficient and MYC-dependent hematological cancer cells by suppression of the paralogue p300. CBP/p300 BRD inhibitor could also prevent its coactivator function at AR, thereby potentially inhibit growth of AR-dependent prostate cancer cells. Thus, targeting CBP/p300 represents an attractive approach for developing personalized therapies.

Experimental procedures and Results: Multiple potent and selective CBP/p300 BRD inhibitors that are structurally unrelated to known inhibitors have been identified by iterative medicinal chemistry and SAR based approaches. The lead compound, AU-18069 was optimized towards attaining good potency, physicochemical properties and DMPK profile. AU-18069 potently inhibited viability and proliferation of a wide range of cell lines derived from prostate cancer, CBP mutant and MYC-dependent hematological cancers and demonstrated improved PK profile in rodent models in comparison with a compound, currently in clinical trials. Excellent efficacy with significant tumor growth inhibition (TGI) was observed in MV4-11 xenograft model at well-tolerated doses along with downregulation of cMYC in a single dose PK-PD study. AU-18069 also showed modulation of different immune phenotypes including CD4+ T cell subsets.

In summary, our lead candidate AU-18069 demonstrated that selective CBP/p300 bromodomain inhibitors are potent in models of hematologic malignancies and solid tumors in vitro and in vivo. Further evaluation of immune activation potential, efficacy studies in various xenograft models, long term toxicological evaluation in different species and other IND enabling studies are in progress.

Citation Format: Chandrasekhar Abbineni, Saravanan Thiyagarajan, Ramesh S Senaiar, Subhendu Mukherjee, Mahaboobi Jaleel, Sivapriya Marappan, Raghavendra N R, Girish Aggunda Renukappa, Aravind A B, Naveen Kumar R, Venkata Siva Reddy, Asha Babu, Akhila Srinivas, Prasad Yadlapalli, Suraj T Gore, Pathange Hemasankar, Mamon Dey, Samiulla D S, Chandranath D Naik, Thomas Antony, Kavitha Nellore, Shekar Chelur, Girish Daginakatte, Mikko Myllymäki, Gerd Wohlfahrt, Murali Ramachandra, Susanta Samajdar. Evaluation of AU-18069, a novel small molecule CBP/p300 bromodomain inhibitor for the treatment of cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1143.