Design, Synthesis, and Characterization of I‑BET567, a Pan-Bromodomain and Extra Terminal (BET) Bromodomain Oral Candidate

Through regulation of the epigenome,
the bromodomain and extra
terminal (BET) family of proteins represent important therapeutic
targets for the treatment of human disease. Through mimicking the
endogenous N-acetyl-lysine group and disrupting the
protein–protein interaction between histone tails and the bromodomain,
several small molecule pan-BET inhibitors have progressed to oncology
clinical trials. This work describes the medicinal chemistry strategy
and execution to deliver an orally bioavailable tetrahydroquinoline
(THQ) pan-BET candidate. Critical to the success of this endeavor
was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors
within the GSK collection which enabled identification of appropriate
lipophilicity space to deliver compounds with a higher probability
of desired oral candidate quality properties. SAR knowledge was leveraged
via Free–Wilson analysis within this design space to identify
a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy
in mouse models of oncology and inflammation.