1360921-60-3Relevant articles and documents
Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7
Marineau, Jason J.,Hamman, Kristin B.,Hu, Shanhu,Alnemy, Sydney,Mihalich, Janessa,Kabro, Anzhelika,Whitmore, Kenneth Matthew,Winter, Dana K.,Roy, Stephanie,Ciblat, Stephane,Ke, Nan,Savinainen, Anneli,Wilsily, Ashraf,Malojcic, Goran,Zahler, Robert,Schmidt, Darby,Bradley, Michael J.,Waters, Nigel J.,Chuaqui, Claudio
, p. 1458 - 1480 (2021/11/18)
CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
INHIBITORS OF CYCLIN-DEPENDENT KINASE 7 (CDK7)
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Paragraph 115-116, (2020/05/28)
The present invention provides various compositions, including compounds of Formula (I) or (la), or a species thereof, and pharmaceutically acceptable salts, solvates (e.g., hydrates), stereoisomer, tautomers, isotopic and other specified forms thereof. Also provided are methods (or uses) and kits involving the compounds or pharmaceutically acceptable compositions containing them for treating or preventing a disease (e.g., a proliferative disease such as cancer) in a subject. Administration of a compound or pharmaceutical composition described herein is expected to inhibit cyclin-dependent kinase 7 (CDK7), and thereby, induce apoptosis in tumor cells in the subject.
