2. Academic Validation
  3. Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors

Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors

  • Bioorg Med Chem Lett. 2021 Jan 1:31:127710. doi: 10.1016/j.bmcl.2020.127710.
Hao-Yue Xiang 1,  Jian-Yang Chen 2,  Xia-Juan Huan 2,  Yi Chen 3,  Zhao-Bing Gao 4,  Jian Ding 2,  Ze-Hong Miao 5,  Chun-Hao Yang 6
Affiliations

Affiliations

  • 1 College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
  • 3 Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
  • 4 Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: [email protected].
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: [email protected].
PMID: 33246105 DOI: 10.1016/j.bmcl.2020.127710
Abstract

A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CC50s of 340 and 106 nM respectively. The PK property of 15b was also investigated here.

Keywords

Antiproliferative; Cancer; PARP inhibitors; Pyrrolo[12-b]pyridazine.

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