Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship

Paola Vianello, Luca Sartori, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Oronza A. Botrugno, Paola Dessanti, Saverio MinucciStefania Vultaggio, Elisa Zagarrí, Mario Varasi, Ciro Mercurio

Research output: Contribution to journalArticle

Abstract

The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described (Part 1, DOI 10.1021.acs.jmedchem.6b01018) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.

Original languageEnglish
Pages (from-to)1693-1715
Number of pages23
JournalJournal of Medicinal Chemistry
Volume60
Issue number5
DOIs
Publication statusPublished - Mar 9 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Vianello, P., Sartori, L., Amigoni, F., Cappa, A., Fagá, G., Fattori, R., Legnaghi, E., Ciossani, G., Mattevi, A., Meroni, G., Moretti, L., Cecatiello, V., Pasqualato, S., Romussi, A., Thaler, F., Trifiró, P., Villa, M., Botrugno, O. A., Dessanti, P., ... Mercurio, C. (2017). Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship. Journal of Medicinal Chemistry, 60(5), 1693-1715. https://doi.org/10.1021/acs.jmedchem.6b01019