2. Academic Validation
  3. Synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidines: Discovery of a selective inhibitor of JAK1 JH2 pseudokinase and VPS34

Synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidines: Discovery of a selective inhibitor of JAK1 JH2 pseudokinase and VPS34

  • Bioorg Med Chem Lett. 2020 Jan 15;30(2):126813. doi: 10.1016/j.bmcl.2019.126813.
Justin D Singleton 1,  Reuben Dass 1,  Nathaniel R Neubert 2,  Rachel M Smith 2,  Zak Webber 2,  Marc D H Hansen 2,  Matt A Peterson 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA.
  • 2 Department of Physiology & Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
  • 3 Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA. Electronic address: matt_peterson@byu.edu.
PMID: 31831383 DOI: 10.1016/j.bmcl.2019.126813
Abstract

A series of novel 3,6-di-substituted or 3-substituted pyrazolo[1,5-a]pyrimidines were prepared via a microwave-assisted approach that generated a broad array of derivatives in good yields (20-93%, ave. = 59%). The straightforward synthesis involved sequential treatment of commercially-available acetonitrile derivatives with DMF-dimethylacetal (120 °C, 20 min), followed by treatment with NH2NH2·HBr (120 °C, 20 min), and 1,1,3,3-tetramethoxypropane or 2-aryl-substituted malondialdehdyes (120 °C, 20 min). Compounds were screened for antimitotic activities against MCF7 breast Cancer and/or A2780 ovarian Cancer cell lines in vitro. The most active compounds exhibited EC50 values ranging from 0.5 to 4.3 μM, with the 3-(4-(trifluoromethyl)phenyl)-6-[4-(2-(piperidin-1-yl)ethoxy]phenyl analogue (34e) and the 3-(2-fluorophenyl)-6-[4-(2-(4-methylpiperizin-1-yl)ethoxy]phenyl analogue (35a) being two to three fold more active than Compound C (Dorsomorphin) in A2780 and MCF7 assays, respectively. Importantly, a monosubstituted 3-(benzothiazol-2-yl) derivative (13) was equipotent with the more synthetically challenging 3,6-disubstituted derivatives (34a-e and 35a-e), and exhibited a promising and unique selectivity profile when screened against a panel consisting of 403 protein kinases (Kinomescan™ selectivity score = 0.005, Kd = 0.55 ± 0.055 μM and 0.410 ± 0.20 μM for JAK1 JH2 pseudokinase and Vps34, respectively).

Keywords

JAK1 JH2 pseudokinase inhibitor; Microwave assisted synthesis; Pyrazolo[1,5-a]pyrimidines; VPS34 kinase inhibitor.

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