CDK9 inhibitors in cancer research

Huang, Zhi; Wang, Tianqi; Wang, Cheng; Fan, Yan

doi:10.1039/d2md00040g

Cited by 10 publications

(4 citation statements)

References 160 publications

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“…a compared to others tested. The 3-chloro variant(29) did not show significantly improved activity against CDK9. Further alkyl variants, including 2-methylpropyl (compounds 30 and 31), failed to show improvement beyond 28.…”

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confidence: 81%

“…(1S,3S)-N3- pyrazolo [1,5-a]pyrimidin-7-yl]cyclopentane-1,3-diamine Hydrochloride (29). To a stirred solution of tert-butyl compound 29b (80 mg, 0.190 mmol; see Supporting Information) in 1,4-dioxane (6.40 mL) was added 4 M HCl−dioxane (0.5 mL, 2 mmol) at 0 °C and stirred at rt for 2 h. The reaction mixture was evaporated in vacuo, and the resulting solid was triturated with pentane (3 × 2 mL) and ether (2 × 2 mL).…”

Section: -Chloro-5-(1-ethylpropyl)pyrazolo[15-a]pyrimidine (49)mentioning

confidence: 99%

“…There are several CDK9 inhibitors, each with varying CDK selectivity profiles, currently being evaluated in the clinic, including atuveciclib, VIP152, AZD4573, PRT2527, and GFH009, that aim to attenuate transcriptional deregulation. 28,29 Interestingly, all of these compounds rely on intravenous (i.v.) administration.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Transcriptional initiation begins with MYC engaging E-box sites and recruiting the RNAP II complex, which is subsequently paused for further complex assembly. , CDK9 releases this paused state by phosphorylating the RNAP II Ser2 and allowing transcriptional elongation to proceed, making CDK9 an attractive target to attenuate unchecked transcriptional addiction to deregulated MYC. There are several CDK9 inhibitors, each with varying CDK selectivity profiles, currently being evaluated in the clinic, including atuveciclib, VIP152, AZD4573, PRT2527, and GFH009, that aim to attenuate transcriptional deregulation. , Interestingly, all of these compounds rely on intravenous (i.v.) administration.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers

Freeman,

Hopkins,

Mikochik

et al. 2023

J. Med. Chem.

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Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

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confidence: 81%

Section: -Chloro-5-(1-ethylpropyl)pyrazolo[15-a]pyrimidine (49)mentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%