2. Academic Validation
  3. b-Annulated 1,4-dihydropyridines as Notch inhibitors

b-Annulated 1,4-dihydropyridines as Notch inhibitors

  • Bioorg Med Chem Lett. 2018 Nov 1;28(20):3363-3367. doi: 10.1016/j.bmcl.2018.09.002.
Jorge E Gómez-Galeno 1,  Cecilia Hurtado 2,  Jiongjia Cheng 3,  Ceren Yardimci 3,  Mark Mercola 2,  John R Cashman 3
Affiliations

Affiliations

  • 1 Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, United States. Electronic address: jorge.gomezgaleno@gmail.com.
  • 2 Cardiovascular Institute and Department of Medicine, Stanford University, 300 Pasteur Drive, MC-5501, Stanford, CA 94305, United States.
  • 3 Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, United States.
PMID: 30201292 DOI: 10.1016/j.bmcl.2018.09.002
Abstract

The Notch signaling pathway is involved in cell proliferation and differentiation, and has been recognized as an active pathway in regenerating tissue and cancerous cells. Notch signaling inhibition is considered a viable approach to the treatment of a variety of conditions including colorectal Cancer, pancreatic Cancer, breast Cancer and metastatic melanoma. The discovery that the b-annulated dihydropyridine FLI-06 (1) is an inhibitor of the Notch pathway with an EC50 ≈ 2.5 μM prompted us to screen a library of related analogs. After structure activity studies were conducted, racemic compound 7 was identified with an EC50 = 0.36 μM. Synthesis of individual enantiomers provided (+)-7 enantiomer with an EC50 = 0.13 μM, or about 20-fold the potency of 1.

Keywords

Colorectal cancer; Dihydropyridines; Notch; Notch signaling.

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