Abstract 4114: Evaluation of AU-18069, a novel small molecule CBP/p300 bromodomain inhibitor for the treatment of cancers
Authors: Abbineni Chandrasekhar , Thiyagarajan Saravanan , A B Aravind , Dhudashiya Amit A , Marappan Sivapriya , Kumar R Naveen , N R Raghavendra , Dey Mamon , Kumar Avinash , B V Uma Bharathi , Renukappa Girish Aggunda , Reddy N Venkata Siva , Babu Asha , Shetty Aakanksha J , A Amith , Rao K Narasimha , Gore Suraj T , Jaleel Mahaboobi , Senaiar Ramesh S , Nataraj Vijaya Shankar , Mukherjee Subhendu , D S Samiulla , Antony Thomas , Daginakatte Girish , Eswarappa Rajesh , Nellore Kavitha , Chelur Shekar , Ramachandra Murali , Samajdar Susanta 
Published: June 2022

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 an oncogenic role in a variety of cancers. Functional synthetic lethal screens have identified preferential killing in CBP-deficient and/or MYC-dependent hematological cancer cells by suppression of the paralogue p300. CBP/p300 BRD inhibitor could also prevent AR and ER signaling, thereby potentially inhibiting growth of AR and ER -dependent cancer cells. Thus, targeting CBP/p300 represents an attractive approach for developing personalized cancer therapies.

Experimental Results: Multiple potent and selective CBP/p300 BRD inhibitors that are structurally unrelated to known inhibitors were identified by iterative medicinal chemistry and SAR based approaches. The lead compound AU-18069 was optimized towards attaining good potency, selectivity, physicochemical properties and DMPK profile. AU-18069 potently inhibited proliferation of a wide range of cell lines derived from prostate cancer, breast cancer and CBP mutant/MYC-dependent hematological cancers. The lead compound demonstrated good PK profile in rodents as well as in dogs. Excellent anti-tumor efficacy was achieved in leukemia and lymphoma xenograft models at well-tolerated doses. Significant downregulation of c-Myc was observed in a single dose PK-PD study.

Conclusion: Lead candidate AU-18069 demonstrated that selective CBP/p300 bromodomain inhibitors are efficacious in models of hematologic malignancies and solid cancers in vitro and in vivo. Further evaluation of efficacy in other xenograft models, as a single agent as well as in combination with other agents is planned. Long term toxicological and safety pharmacology evaluation in different species and other IND enabling studies are in progress to support progression of this compound to clinical trials.

Citation Format: Chandrasekhar Abbineni, Saravanan Thiyagarajan, Aravind A B, Amit A Dhudashiya, Sivapriya Marappan, Naveen Kumar R, Raghavendra N R, Mamon Dey, Avinash Kumar, Uma Bharathi B V, Girish Aggunda Renukappa, N Venkata Siva Reddy, Asha Babu, Aakanksha J Shetty, Amith A, Narasimha Rao K, Suraj T Gore, Mahaboobi Jaleel, Ramesh S Senaiar, Vijaya Shankar Nataraj, Subhendu Mukherjee, Samiulla D S, Thomas Antony, Girish Daginakatte, Rajesh Eswarappa, Kavitha Nellore, Shekar Chelur, 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 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4114.