Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatm...
Basic Information
ID: ALA5036331
Journal: J Med Chem
Title: 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.
Authors: Lücking U, Kosemund D, Böhnke N, Lienau P, Siemeister G, Denner K, Bohlmann R, Briem H, Terebesi I, Bömer U, Schäfer M, Ince S, Mumberg D, Scholz A, Izumi R, Hwang S, von Nussbaum F.
Abstract: 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.
CiteXplore: 34264057
DOI: 10.1021/acs.jmedchem.1c01000
Patent ID: ┄