hki-272 and Lung-Neoplasms

Covalent drugs have made a major impact on human health but until recently were shunned by the pharmaceutical industry over concerns about the potential for toxicity. A resurgence has occurred driven by the clinical success of targeted covalent inhibitors (TCIs), with eight drugs approved over the past decade. The opportunity to create unique drugs by exploiting the covalent mechanism of action has enabled clinically decisive target product profiles to be achieved. TCIs have revolutionized the treatment paradigm for non-small-cell lung cancer and chronic lymphocytic leukemia. This Perspective will highlight the clinical and financial success of this class of drugs and provide early insight into toxicity, a key factor that had hindered progress in the field. Further innovation in the TCI approach, including expanding beyond cysteine-directed electrophiles, kinases, and cancer, highlights the broad opportunity to deliver a new generation of breakthrough therapies.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Phosphotransferases; Protein Kinase Inhibitors

On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; ErbB Receptors; Female; Humans; Lung; Lung Neoplasms; Mice; Mice, Nude; Molecular Docking Simulation; Piperidines; Point Mutation; Protein Conformation; Protein Kinase Inhibitors; Rats, Sprague-Dawley

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays