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.