1. Academic Validation
  2. Discovery of a novel oral type Ⅰ CDK8 inhibitor against acute myeloid leukemia

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

  • Eur J Med Chem. 2023 May 5;251:115214. doi: 10.1016/j.ejmech.2023.115214.
Xing Xing Zhang 1 Yao Yao Yan 1 Xiao Ma 2 Yun Xiao 1 Cen Cen Lei 1 Yu Meng Wang 1 Chao Liu 3 Quan Wang 1 Xing Tao Zhang 4 Wen Dan Cheng 5 Xin Hua Liu 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
  • 2 Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China.
  • 3 School of Biological and Food Engineering, Suzhou University, Suzhou, 234000, PR China.
  • 4 School of Biological and Food Engineering, Suzhou University, Suzhou, 234000, PR China. Electronic address: hsxyzxt@163.com.
  • 5 Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China. Electronic address: sunyccc@126.com.
  • 6 School of Biological and Food Engineering, Suzhou University, Suzhou, 234000, PR China; School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China. Electronic address: xhliuhx@163.com.
Abstract

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 μM) 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 addition, 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.

Keywords

AML; CDK8 inhibitor; STAT-1; STAT-5; pyrrolo[2,3-b]pyridine.

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