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Discovery of novel and potent CDK8 inhibitors for the treatment of acute myeloid leukaemia.

ABSTRACT: It has been reported that CDK8 plays a key role in acute myeloid leukaemia. Here, a total of 40 compounds were rational designed and synthesised based on the previous SAR. Among them, compound 12 (3-(3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide) showed the most potent inhibiting activity against CDK8 with an IC₅₀ value of 39.2 ± 6.3 nM and anti AML cell proliferation activity (molm-13 GC₅₀ = 0.02 ± 0.01 μM, MV4-11 GC₅₀ = 0.03 ± 0.01 μM). Mechanistic studies revealed that this compound 12 could inhibit the phosphorylation of STAT-1 and STAT-5. Importantly, compound 12 showed relative good bioavailability (F = 38.80%) and low toxicity in vivo. This study has great significance for the discovery of more efficient CDK8 inhibitors and the development of drugs for treating AML in the future.

SUBMITTER: Chen Z

PROVIDER: S-EPMC10810651 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature

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Discovery of novel and potent CDK8 inhibitors for the treatment of acute myeloid leukaemia.

Chen Zhuoying Z Wang Quan Q Yan Yao Yao YY Jin Dalong D Wang Yumeng Y Zhang Xing Xing XX Liu Xin Hua XH

Journal of enzyme inhibition and medicinal chemistry 20240123 1

It has been reported that CDK8 plays a key role in acute myeloid leukaemia. Here, a total of 40 compounds were rational designed and synthesised based on the previous SAR. Among them, compound 12 (3-(3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide) showed the most potent inhibiting activity against CDK8 with an IC50 value of 39.2 ± 6.3 nM and anti AML cell proliferation activity (molm-13 GC50 = 0.02 ± 0.01 μM, MV4-11 GC50 = 0.03 ± 0.01 ...[more]

PMID: 38258519

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