Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer

Selective
inhibition of exclusively transcription-regulating positive
transcription elongation factor b/CDK9 is a promising new approach
in cancer therapy. Starting from atuveciclib, the first selective
CDK9 inhibitor to enter clinical development, lead optimization efforts
aimed at identifying intravenously (iv) applicable CDK9 inhibitors
with an improved therapeutic index led to the discovery of the highly
potent and selective clinical candidate VIP152. The evaluation of
various scaffold hops was instrumental in the identification of VIP152,
which is characterized by the underexplored benzyl sulfoximine group.
VIP152 exhibited the best preclinical overall profile in vitro and
in vivo, including high efficacy and good tolerability in xenograft
models in mice and rats upon once weekly iv administration. VIP152
has entered clinical trials for the treatment of cancer with promising
longterm, durable monotherapy activity in double-hit diffuse large
B-cell lymphoma patients.