2. Academic Validation
  3. Discovery of Highly Potent and Selective Matrix Metalloproteinase-7 Inhibitors by Hybridizing the S1' Subsite Binder with Short Peptides

Discovery of Highly Potent and Selective Matrix Metalloproteinase-7 Inhibitors by Hybridizing the S1' Subsite Binder with Short Peptides

  • J Med Chem. 2022 Oct 13;65(19):13253-13263. doi: 10.1021/acs.jmedchem.2c01088.
Hideaki Tabuse 1,  Kumi Abe-Sato 1,  Harumi Kanazawa 1,  Miyoko Yashiro 2,  Yunoshin Tamura 2,  Masafumi Kamitani 2,  Kosuke Hitaka 3,  Emi Gunji 3,  Akiko Mitani 3,  Naoki Kojima 3,  Yusuke Oka 1
Affiliations

Affiliations

  • 1 Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama 331-9530, Japan.
  • 2 Discovery Technologies Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama 331-9530, Japan.
  • 3 Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama 331-9530, Japan.
PMID: 36137271 DOI: 10.1021/acs.jmedchem.2c01088
Abstract

Matrix metalloproteinase-7 (MMP-7) has emerged as a protein playing important roles in both physiological and pathophysiological processes. Despite the growing interest in MMP-7 as a potential therapeutic target for diseases including Cancer and fibrosis, potent and selective MMP-7 inhibitors have yet to be identified. Compound 1, previously reported by Edman and co-workers, binds to the S1' subsite of MMP-7, exhibiting moderate inhibitory activity and selectivity. To achieve both higher inhibitory activity and selectivity, we conceived hybridizing 1 with short Peptides. The initially designed compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over other MMP subtypes.

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