Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation PMID: 37952596

ADC Targets in Oncology

2026-04-10

Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation

Bioorg Med Chem Lett. 2023 Nov 10:97:129541. doi: 10.1016/j.bmcl.2023.129541.

Rie Nishikawa-Shimono ¹ , Motoi Kuwabara ¹ , Sho Fujisaki ¹ , Daisuke Matsuda ² , Mayumi Endo ³ , Masafumi Kamitani ³ , Aya Futamura ¹ , Yusaku Nomura ¹ , Toru Yamaguchi-Sasaki ¹ , Tetsuya Yabuuchi ¹ , Chitose Yamaguchi ¹ , Nozomi Tanaka-Yamamoto ¹ , Shunya Satake ¹ , Kumi Abe-Sato ¹ , Kosuke Funayama ¹ , Mayumi Sakata ³ , Shinji Takahashi ⁴ , Koga Hirano ⁴ , Takuya Fukunaga ³ , Yoriko Uozumi ³ , Sayaka Kato ³ , Yunoshin Tamura ³ , Tomoaki Nakamori ³ , Masashi Mima ³ , Chiemi Mishima-Tsumagari ³ , Dai Nozawa ¹ , Yudai Imai ¹ , Taiji Asami ⁵

Affiliations

Abstract

Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.

Keywords

Fragile X syndrome; Indole derivatives; Inhibitor of proMMP-9 activation; Matrix metalloproteinase-9; Structure-based drug design.