Discovery of a novel oral type I CDK8 inhibitor against acute myeloid leukemia

CDK8 plays a key role in acute myeloid leukemia, colorectal cancer and other cancers. Here, a total of 54 compounds were designed and synthesized. Among them, the most potent one compound 43 (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide), a novel CDK8 I inhibitor, showed strong inhibitory activity against CDK8 (IC50 = 51.9 nM), good kinase selectivity, good anti AML cell proliferation activity (molm-13 GC50 = 1.57 +/- 0.59 mu M) and low toxicity in vivo (acute toxicity: 2000 mg/kg). Further mechanistic studies revealed that this compound could target CDK8 and then phosphorylate STAT-1 and STAT-5 thereby inhibiting of AML cell proliferation. In addi-tion, compound 43 showed relatively good bioavailability (F = 28.00%) and could inhibit the growth of AML tumors in a dose-dependent manner in vivo. This study facilitates the further development of more potent CDK8 inhibitors for the treatment of the AML.

Automated summary

CDK8, a key player in acute myeloid leukemia and colorectal cancer, was targeted using a novel compound 43. The compound demonstrated strong inhibitory activity against CDK8, good selectivity, and anti-proliferative effects on AML cells. Mechanistic studies revealed that compound 43 directly targeted CDK8, leading to the inhibition of AML cell proliferation through phosphorylation of STAT-1 and STAT-5. In addition, compound 43 showed good bioavailability and dose-dependent inhibition of AML tumor growth in vivo. This study contributes to the development of more potent CDK8 inhibitors for AML treatment.