Abstract 6043: Discovery and characterization of a p300-selective degrader with potent anti-tumor activity in CBP mutant cancers

Abstract

Abstract Although precision medicine strategies for the treatment of human cancers are clinically successful, they have also revealed that only a small fraction of cancers carry actionable alterations in oncogenic drivers. To expand the druggable genome while maintaining an emphasis on genetically targeted therapies, recent efforts have focused on exploiting synthetic lethal relationships. Paralogous protein pairs are particularly compelling targets in this context due to the clear mechanistic basis for the synthetic lethality. As such, functional genomics screens as well as work from Ogiwara et al. have shown compelling rationale for targeting the histone acetylase transferase p300 in the context of CBP-deficient cancer types. We discovered potent heterobifunctional degraders with demonstrated selectivity for p300 over CBP. Our compound exhibits degradation of p300 within 2 hours (DC50 < 10nM, Dmax > 90%) with minimal impact on CBP through 48 h (DC50 >1uM, Dmax = 30%). Utilizing CRISPR-generated isogenic cell lines depleted for either CBP or p300, we observed significant growth inhibition in CBP knockout (KO) cells (gIC50 = 17nM) with minimal impact on growth of p300 KO (gIC50 = >10uM) or parental wild-type cells (gIC50 > 10uM). This translated to downstream pharmacology, where we observed a rapid and potent inhibition of global H3K27 acetylation in the CBP deficient context but a significantly attenuated response in p300 deleted or parental cells. We subsequently employed computational methods to identify and characterize CBP alterations, defining a putative loss-of-function (LoF) phenotype and confirming this sensitivity pharmacologically in cancer cell types harboring these endogenous mutations. Results mirrored what we observed with CBP depletion in these endogenous CBP LoF cell lines, with potent growth inhibition seen in multiple cell lines including LK-2 (gIC50 = 8nM), H1703 (gIC50 = 9nM), and TE-8 cells (gIC50 = 23nM). To confirm the in vitro results in an in vivo setting, we evaluated the response in mice harboring H1703 xenografts. Once daily oral administration of our compound led to almost complete degradation of p300 within H1703 xenograft tumors, resulting in a pronounced inhibition of tumor growth. Lastly, we profiled p300 degradation in human bone marrow derived myeloid progenitor colony-forming assays where we observed a significant reduction in toxicity (IC50 = 3.9uM) compared to a dual CBP/p300 inhibitor (IC50 = 121nM) or degrader (IC50 = 16nM), supporting the hypothesis that a p300-specific mechanism will offer an improved therapeutic index while maintaining anti-tumor efficacy in a biomarker population Taken together, our results suggest that a p300-selective degrader has the potential to serve as an effective therapeutic modality in CBP-mutated cancers. Citation Format: Mike R. Russell, Cassandra L. Lowenstein, Xuqing Zhang, Jeremy Roach, Jianing Song, Rakesh Nagilla, Nathan Kendsersky, Shreyas Joshi, Peter Orth, Matt Tudor, Qiaolin Deng, Clemente Aguilar-Bonavides, Elham Behshad, Sudeep Banjade, Zhihua Sui, Corey Strickland, Larry Jolivette, Helai P. Mohammad. Discovery and characterization of a p300-selective degrader with potent anti-tumor activity in CBP mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6043.