Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation

Proteolysis-targeting chimeras (PROTACs) have transformed the concept of chemical intervention in biological systems by co-opting the ubiquitin–proteasome system to selectively degrade proteins. A key...

pubs.acs.org

Discovery and Optimization of Orally Bioavailable Heterobifunctional Degraders of KAT2A/B for the Treatment of Cancer

Using our proprietary AI/ML platform AURIGIN that maps tumor cells against normal developmental pathways, we identify targets that have been hijacked by cancerous cells to maintain a highly plastic proliferative cell state. We identified the histone acetyltransferase KAT2A as a key driver of tumor cell plasticity in a subset of acute myeloid leukemias (AML) and neuroendocrine carcinomas such as small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Herein, we describe our development of heterobifunctional degraders of KAT2A/B, resulting in compound 7, a picomolar degrader that is capable of inhibiting proliferation of AML (MOLM-13) and SCLC (NCI–H1048) cell lines in vitro and demonstrates robust degradation of KAT2A in NCI–H1048 engrafted mice when administered IP. Building on the success of compound 7, we subsequently developed orally bioavailable degraders of KAT2A/B, exemplified by compound 24, that achieved an oral bioavailability of 47% in mice.

pubs.acs.org