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
  • 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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