Abstract
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.
Highlights
Cyclin-dependent kinase 7 (CDK7) is a serine-threonine kinase that plays key roles in both transcription and regulation of the cell cycle
Selective drug targeting within the cyclin-dependent kinase (CDK) family has historically proven challenging, but the recent clinical success of CDK4/6 inhibitors provides an example of the potential benefits of selective CDK inhibition.[4]
SY-5609 is capable of inhibiting CDK7 in vivo and demonstrates regression in murine tion
Summary
Cyclin-dependent kinase 7 (CDK7) is a serine-threonine kinase that plays key roles in both transcription and regulation of the cell cycle. Appropriate temporal activation of these CDKs is responsible for coordinating the progression of cells through the cell cycle.[4] CDK7 has been shown to activate transcriptional CDKs.[5,6] The CDK7 trimer is found in the multisubunit general transcription factor TFIIH complex As part of this complex, CDK7 phosphorylates the C-terminal domain (CTD) of the largest subunit RBP1 of RNA polymerase II (PolII) at Ser[5] and Ser[7] of its YSPTSPS heptad repeat. Previous experience with the covalent inhibitor SY-1365,8 the first selective CDK7 inhibitor in clinical trials, demonstrated the potential of CDK7 inhibition in a variety of cancer types and inspired development of a highly selective and orally available CDK7 inhibitor This was accomplished via a medicinal chemistry program which optimized a series of highly potent, Special Issue: New Horizons in Drug Discovery Understanding and Advancing Kinase Inhibitors
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