Gaurav Sheth, Shailesh R Shah, Prabal Sengupta, Tushar Jarag, Sabbirhusen Chimanwala, Kalapatapu V V M Sairam, Vaibhav Jain, Rashmi Talwar, Avinash Dhanave, Mehul Raviya, Harendra Jha, Rajasekhar Reddy Chilakala, Trinadha Rao Chitturi
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Strategic Design and Development of Indole-Based Compounds as Potent malic Enzyme 3 Inhibitors for Pancreatic Tumor Therapy.
Malic enzyme 3 (ME3) plays a critical role in the survival of SMAD4-/-/ME2-/- pancreatic ductal adenocarcinoma (PDAC) cells by supporting energy production and maintaining redox homeostasis. Therefore, targeting ME3 with small-molecule inhibitors presents a promising therapeutic strategy for PDAC patients with SMAD4/ME2 deletions. Building upon our previously developed ME3 inhibitor, a systematic exploration of the structure-activity relationship (SAR) was undertaken to identify novel chemotypes. This effort led to the discovery of a new series of indole-substituted piperazine carboxamides with potent ME3 inhibitory activity, among which compound 13 emerged to be the most effective in PDAC cell lines. Furthermore, the synergistic effects of the newly identified compound 13 with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib were evaluated on Hs766T cells which revealed a significant synergism of this combination.
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Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies.
ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs.
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