2. Academic Validation
  3. 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: [email protected].
  • 5 Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China. Electronic address: [email protected].
  • 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: [email protected].
PMID: 36889252 DOI: 10.1016/j.ejmech.2023.115214
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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