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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
Journal of medicinal chemistry, 01/2022, Letnik: 65, Številka: 2Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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