WZ4002 News - LARVOL Sigma

|||||||||| Xalkori (crizotinib) / Pfizer, KU-55933 / AstraZeneca, WZ4002 - Dana / Farber Cancer Institute
Preclinical, Journal: ATM inhibition blocks glucose metabolism and amplifies the sensitivity of resistant lung cancer cell lines to oncogene driver inhibitors. (Pubmed Central) - Nov 7, 2023
Inhibition of ATM reduced both glycolytic enzymes and OXPHOS levels in oncogene-driven cancer cells and enhanced apoptosis induced by driver inhibitors thus highlighting the possibility to use ATM and the driver inhibitors in combined regimens of anticancer therapy in vivo.

|||||||||| Gilotrif (afatinib) / Boehringer Ingelheim, Vizimpro (dacomitinib) / Pfizer, WZ4002 - Dana / Farber Cancer Institute
Journal: Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC). (Pubmed Central) - Jan 1, 2022
To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed...Among them, compounds 2i (IC 0.171 µM) and 11h (IC 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay...The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.

|||||||||| Xalkori (crizotinib) / Pfizer, WZ4002 - Dana / Farber Cancer Institute
Journal, IO biomarker: Non-Canonical Role of PDK1 as a Negative Regulator of Apoptosis through Macromolecular Complexes Assembly at the ER-Mitochondria Interface in Oncogene-Driven NSCLC. (Pubmed Central) - Aug 28, 2021
Co-immunoprecipitation studies showed that PDK1 interacts with PKM2, Bcl-2 and Bcl-xL, forming macromolecular complexes at the ER-mitochondria interface. Our findings showed that downregulation of PDK1 is able to potentiate the effects of TKIs through the disruption of macromolecular complexes involving PKM2, Bcl-2 and Bcl-xL.

|||||||||| Tagrisso (osimertinib) / AstraZeneca, WZ4002 - Dana / Farber Cancer Institute
Preclinical, Journal: Efficacy of the CDK7 Inhibitor on EMT-Associated Resistance to 3rd Generation EGFR-TKIs in Non-Small Cell Lung Cancer Cell Lines. (Pubmed Central) - Jun 26, 2021
In addition, THZ1 treatment led to drug-tolerant, EMT-related resistant cells, and these THZ1-tolerant cells partially recovered their sensitivity to 3rd generation EGFR-TKIs. Taken together, EMT was associated with acquired resistance to 3rd generation EGFR-TKIs, and CDK7 inhibitors could potentially be used as a therapeutic strategy to overcome EMT associated EGFR-TKI resistance in NSCLC.

|||||||||| Journal: Insight into Binding Mechanisms of EGFR Allosteric Inhibitors using Molecular Dynamics Simulations and Free Energy Calculations. (Pubmed Central) - Jul 21, 2020
The new-generation inhibitors such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to Cys 797, but ultimately lose their efficacy upon the emergence of the C797S mutation that abolishes the covalent bonding...Allosteric inhibitors EAI001 and EAI045 are a new type of EGFR inhibitors that bind to EGFR away from the ATP-binding site and not relying on Cys 797. In the present study, molecular dynamics simulations and free energy calculations were carried out for EAI001 and EAI045 in complex with EGFR, revealing the detailed inhibitory mechanism of EAI001 and EAI045 as EGFR allosteric inhibitor, which was expected to provide a basis for rational drug design of the EGFR allosteric inhibitors.

|||||||||| WZ4002 - Dana / Farber Cancer Institute
Journal: Identification and Optimization of Novel Cathepsin C Inhibitors Derived from EGFR Inhibitors. (Pubmed Central) - May 29, 2020
In the course of developing the biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we herein unexpectedly discovered that the epidermal growth factor receptor irreversible inhibitor WZ4002 also functioned as a low micromolar inhibitor of cathepsin C (CatC), a promising target for the treatment of numerous inflammatory and autoimmune diseases...In vivo studies revealed that compound 22 clearly showed the ability of CatC inhibition, consequently led to efficient inhibition on the activation of downstream neutrophil serine proteases in both bone marrow and blood. The overall excellent profile of compound 22 made it an interesting candidate for further pre-clinical investigation.

|||||||||| Tykerb (lapatinib) / Novartis, WZ4002 - Dana / Farber Cancer Institute
Journal: Monitoring activities of receptor tyrosine kinases using a universal adapter in genetically encoded split TEV assays. (Pubmed Central) - Mar 27, 2019
The sensitivity and robustness of the RTK recruitment assays were validated in dose-dependent inhibition assays using the ERBB family-selective antagonists lapatinib and WZ4002. The RTK split TEV recruitment assays also qualify for high-throughput screening approaches, suggesting that the artificial adapter may be used as universal adapter in cell-based profiling assays within pharmacological intervention studies.



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