2 research outputs found
Thieno[3,2‑<i>b</i>]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure–Activity Relationship
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-<i>b</i>]pyrrole-5-carboxamides as novel reversible
inhibitors of KDM1A, whose preliminary exploration resulted in compound <b>2</b> with biochemical IC<sub>50</sub> = 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 <b>46</b>, <b>49</b>, and <b>50</b> showed single-digit nanomolar
IC<sub>50</sub> 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, <b>49</b> and <b>50</b> showed
a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia
cells
Thieno[3,2‑<i>b</i>]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 1: High-Throughput Screening and Preliminary Exploration
Lysine specific demethylase
1 KDM1A (LSD1) regulates histone methylation
and it is increasingly recognized as a potential therapeutic target
in oncology. We report on a high-throughput screening campaign performed
on KDM1A/CoREST, using a time-resolved fluorescence resonance energy
transfer (TR-FRET) technology, to identify reversible inhibitors.
The screening led to 115 hits for which we determined biochemical
IC<sub>50</sub>, thus identifying four chemical series. After data
analysis, we have prioritized the chemical series of <i>N</i>-phenyl-4<i>H</i>-thieno[3, 2-<i>b</i>]pyrrole-5-carboxamide
for which we obtained X-ray structures of the most potent hit (compound <b>19</b>, IC<sub>50</sub> = 2.9 μM) in complex with the enzyme.
Initial expansion of this chemical class, both modifying core structure
and decorating benzamide moiety, was directed toward the definition
of the moieties responsible for the interaction with the enzyme. Preliminary
optimization led to compound <b>90</b>, which inhibited the
enzyme with a submicromolar IC<sub>50</sub> (0.162 μM), capable
of inhibiting the target in cells