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 IC = 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 IC 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.
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, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC = 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 90, which inhibited the enzyme with a submicromolar IC (0.162 μM), capable of inhibiting the target in cells.
The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.
Background: Microarrays have been widely used for the analysis of gene expression and several commercial platforms are available. The combined use of multiple platforms can overcome the inherent biases of each approach, and may represent an alternative that is complementary to RT-PCR for identification of the more robust changes in gene expression profiles.
Background:
Discovery and development of a new drug is a long lasting and expensive
journey that takes around 20 years from starting idea to approval and marketing of new medication.
Despite R&D expenditures have been constantly increasing in the last few years, the number of new
drugs introduced into market has been steadily declining. This is mainly due to preclinical and clinical
safety issues, which still represent about 40% of drug discontinuation. To cope with this issue, a number
of in silico techniques are currently being used for an early stage evaluation/prediction of potential
safety issues, allowing to increase the drug-discovery success rate and reduce costs associated with the
development of a new drug.
Methods:
In the present review, we will analyse the early steps of the drug-discovery pipeline, describing
the sequence of steps from disease selection to lead optimization and focusing on the most common
in silico tools used to assess attrition risks and build a mitigation plan.
Results:
A comprehensive list of widely used in silico tools, databases, and public initiatives that can
be effectively implemented and used in the drug discovery pipeline has been provided. A few examples
of how these tools can be problem-solving and how they may increase the success rate of a drug
discovery and development program have been also provided. Finally, selected examples where the
application of in silico tools had effectively contributed to the development of marketed drugs or clinical
candidates will be given.
Conclusion:
The in silico toolbox finds great application in every step of early drug discovery: (i) target
identification and validation; (ii) hit identification; (iii) hit-to-lead; and (iv) lead optimization. Each
of these steps has been described in details, providing a useful overview on the role played by in silico
tools in the decision-making process to speed-up the discovery of new drugs.
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