1. 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
- Author
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Franz von Nussbaum, Ulrich Lücking, Dirk Kosemund, Stuart Ince, Hans Briem, Philip Lienau, Martina Schäfer, Arne Scholz, Ulf Bömer, Dominik Mumberg, Stuart Hwang, Niels Böhnke, Gerhard Siemeister, Karsten Denner, Ildiko Terebesi, Rolf Bohlmann, and Raquel Izumi
- Subjects
Mice, Nude ,Antineoplastic Agents ,Pharmacology ,Mice ,Structure-Activity Relationship ,Therapeutic index ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Dosing ,Protein Kinase Inhibitors ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Cancer ,Neoplasms, Experimental ,medicine.disease ,Cyclin-Dependent Kinase 9 ,In vitro ,Rats ,Lymphoma ,Clinical trial ,Leukemia, Myeloid, Acute ,Tolerability ,Injections, Intravenous ,Molecular Medicine ,Female ,Drug Screening Assays, Antitumor - 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.
- Published
- 2021