2. Academic Validation
  3. Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors

Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors

  • J Med Chem. 2021 Jan 14;64(1):695-710. doi: 10.1021/acs.jmedchem.0c01705.
Christine Brotherton-Pleiss 1 2,  Peibin Yue 1,  Yinsong Zhu,  Kayo Nakamura 3,  Weiliang Chen 3,  Wenzhen Fu 1 3,  Casie Kubota 1,  Jasmine Chen 1,  Felix Alonso-Valenteen 4,  Simoun Mikhael 4,  Lali Medina-Kauwe 4,  Marcus A Tius 1 2,  Francisco Lopez-Tapia 1 2,  James Turkson 1
Affiliations

Affiliations

  • 1 Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, Hawaii 96813, United States.
  • 2 Medicinal Chemistry Leader, Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, Hawaii 9682, United States.
  • 3 Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, Hawaii 9682, United States.
  • 4 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, United States.
PMID: 33352047 DOI: 10.1021/acs.jmedchem.0c01705
Abstract

We optimized our previously reported proline-based STAT3 inhibitors into an exciting new series of (R)-azetidine-2-carboxamide analogues that have sub-micromolar potencies. 5a , 5o , and 8i have STAT3-inhibitory potencies (IC50) of 0.55, 0.38, and 0.34 μM, respectively, compared to potencies greater than 18 μM against STAT1 or STAT5 activity. Further modifications derived analogues, including 7e , 7f , 7g , and 9k , that addressed cell membrane permeability and Other physicochemical issues. Isothermal titration calorimetry analysis confirmed high-affinity binding to STAT3, with KD of 880 nM ( 7g ) and 960 nM ( 9k ). 7g and 9k inhibited constitutive STAT3 phosphorylation and DNA-binding activity in human breast Cancer, MDA-MB-231 or MDA-MB-468 cells. Furthermore, treatment of breast Cancer cells with 7e , 7f , 7g , or 9k inhibited viable cells, with an EC50 of 0.9-1.9 μM, cell growth, and colony survival, and induced Apoptosis while having relatively weaker effects on normal breast epithelial, MCF-10A or breast Cancer, MCF-7 cells that do not harbor constitutively active STAT3.

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