WZ4002 / Dana-Farber Cancer Institute - LARVOL DELTA

Discovery of potent CRBN-recruiting epidermal growth factor receptor (EGFR) degraders in vitro. (PubMed, Invest New Drugs) - "In this paper, we designed and synthesized a series of small molecule PROTACs targeting EGFR utilizing WZ4002, known for its mutation selectivity, as the warhead...Further analysis through protein immunoblotting revealed that HJM- 17 effectively reduced the expression of EGFRL858R/T790M. These active compounds lay the groundwork for future studies focused on EGFR-targeting PROTACs."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CRBN • EGFR

Repurposing Non-Nucleosidic Reverse Transcriptase Inhibitors (NNRTIs) to Overcome EGFR T790M-Mediated Acquired Resistance in Non-Small Cell Lung Cancer. (PubMed, J Cell Biochem) - "This study investigates the repurposing potential of non-nucleosidic reverse transcriptase inhibitors (NNRTIs), specifically Rilpivirine and Etravirine, as L858R/T790M tyrosine kinase inhibitors for addressing acquired resistance in non-small cell lung cancer (NSCLC). Using in silico molecular docking, Rilpivirine demonstrated a docking score of -7.534 kcal/mol, comparable to established epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like Osimertinib and WZ4002...Enzymatic assays revealed that Rilpivirine inhibited the double mutant epidermal growth factor receptor tyrosine kinase (EGFR TK) with an IC50 value of 54.22 nM and spared the wild-type EGFR TK with an IC50 of 22.52 nM. These findings suggest Rilpivirine's potential as a therapeutic agent for NSCLC with EGFR L858R/T790M mutations."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Discovery of a Therapeutic Agent for Glioblastoma Using a Systems Biology-Based Drug Repositioning Approach. (PubMed, Int J Mol Sci) - "We validated our findings by treating U-138 MG cells with WZ-4002, observing a decrease in CHST2 protein levels and a reduction in cell viability. In summary, our research suggests that the WZ-4002 drug candidate may effectively modulate CHST2 and adjacent genes, offering a promising avenue for developing efficient treatment strategies for GBM patients."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • EGFR • HER-2

ATM inhibition blocks glucose metabolism and amplifies the sensitivity of resistant lung cancer cell lines to oncogene driver inhibitors. (PubMed, Cancer Metab) - "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."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCND1 • PKM

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, Cancers (Basel)) - "H1993 and H1975 cells were stably transfected with scrambled (shCTRL) or PDK1-targeted (shPDK1) shRNA and then treated with MET inhibitor crizotinib (1 µM), double mutant EGFR inhibitor WZ4002 (1 µM) or vehicle for 48 h. The effects of PDK1 knockdown on glucose metabolism and apoptosis were evaluated in untreated and TKI-treated cells. 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."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • PDPK1 • PKM

Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC). (PubMed, Bioorg Chem) - "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."

Journal • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Discovery of a potent dual ALK and EGFR T790M inhibitor (AACR 2018) - "...Several wild-type and mutant-directed inhibitors of both ALK and EGFR have been developed such as the first-generation ALK inhibitor, crizotinib and the first and second generation EGFR inhibitors, gefitinib, erlotinib and afatinib to treat NSCLC. The second generation ALK inhibitors, ceritinib, alectinib and brigatinib and the third generation EGFR inhibitor, osimertinib potently overcome the secondary resistant mutations...Based on our previous effort developing covalent T790M EGFR inhibitor, WZ4002, we have rationally designed and synthesized the potent dual inhibitor of ALK and EGFR, particularly the T790M resistant mutant, by combining the crucial functional groups of known ALK inhibitors ceritinib and brigatinib, and EGFR inhibitors WZ4002 and osimertinib, in the 2,4-diarylaminopyrimidine scaffold...Our lead compound 7c displayed remarkable inhibitory activities against both ALK and EGFR in enzymatic and cellular assays. We demonstrate that 7c is capable of..."

Lymphoma • Non Small Cell Lung Cancer

Efficacy of the CDK7 Inhibitor on EMT-Associated Resistance to 3rd Generation EGFR-TKIs in Non-Small Cell Lung Cancer Cell Lines. (PubMed, Cells) - "We established 3rd generation EGFR-TKI resistant cell lines (H1975/WR and H1975/OR) via repeated exposure to WZ4002 and osimertinib. 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 • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDK7 • EGFR • VIM

Insight into Binding Mechanisms of EGFR Allosteric Inhibitors using Molecular Dynamics Simulations and Free Energy Calculations. (PubMed, J Biomol Struct Dyn) - "Patients harboring most of these mutations respond well to the EGFR inhibitors Gefitinib and Erlotinib initially, but soon develop resistance to them due to the emergence of the gatekeeper mutation T790M. 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."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR mutant lung cancer (Mol Cancer Ther) - PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation & HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib due to HGF gene transfection, gatekeeper T790M mutation & Met amplification, respectively; WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER & PC-9/HGF cells; HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, & HGF-treated H1975 cells to WZ4002, inhibiting EGFR & Met phosphorylation & their downstream molecules; Combined treatment potently inhibited the growth of tumors induced in SCID mice by H1975, HCC827ER & PC-9/HGF cells, without any marked adverse events

Preclinical • Oncology

Identification and Optimization of Novel Cathepsin C Inhibitors Derived from EGFR Inhibitors. (PubMed, J Med Chem) - "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."

Journal • Immunology

WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors (Lab Invest) - Suspended EGFR-mutant lung adenocarcinoma cells depend significantly more on EGFR activation for survival than attached cells do; The tumor cells circulating in vessels, which express mutant-specific EGFR, would be highly susceptible to the combination therapy of WZ4002, ABT-263, & TSA

Preclinical-other • Oncology

Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib (PLoS One) - Both lapatinib-sensitive & lapatinib-resistant ERBB2 mutations were observed; Resistance mutations may also cause secondary in cloned cell lines with clinically observed ERBB2 mutations resistance in lapatinib-treated pts; Lapatinib-resistant ERBB2 mutations were found to be highly resistant towards AEE788 treatment but remained sensitive towards the dual irreversible inhibitors CL-387785 & WZ-4002

Preclinical-other • Breast Cancer • Oncology

Combined EGFR and MEK inhibition prevents the emergence of drug resistance in EGFR mutant non-small cell lung cancer (NSCLC) (AACR 2014) - Presentation time: Monday, Apr 07, 2014, 8:00 AM -12:00 PM; Abstract #1832; “...WZ/TRA significantly reduced the emergence of drug resistant clones compared to each single agent...In models where WZ/TRA was effective, the combination led to increased apoptosis compared to single agents and effective inhibition of ERK signaling...Combination WZ/TRA treatment prevented tumor outgrowth for 24 weeks in 5 EGFR L858R/T790M GEMM mice whereas individual treatments did not."  

Preclinical • Non Small Cell Lung Cancer • Oncology

Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR mutant Lung Cancer. (PubMed) - "Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial co-targeting of EGFR and MEK could significantly impede the development of acquired resistance in mutant EGFR lung cancer."

Preclinical • Biosimilar • Oncology

Nitric oxide donating anilinopyrimidines: Synthesis and biological evaluation as EGFR inhibitors (Eur J Med Chem) - PMID: 23792318; “Compounds 10f-h exhibited potent inhibitory activity against EGFR L858R/T790M and were as potent as WZ4002 in inhibition of H1975 cells harboring EGFR L858R/T790M. Additionally, 10h produced high levels of NO in H1975 cells but not in normal human cells, and its antiproliferative activity was diminished by hemoglobin, an NO scavenger.”

Preclinical • Oncology

Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors. - Bioorg Med Chem - "These compounds also strongly inhibited the proliferation of H1975 non-small cell lung cancer cells bearing EGFR(L858R/T790M), while being significantly less toxic to A431 human epithelial carcinoma cells with overexpressed EGFR(WT). The EGFR kinase inhibitory and antiproliferative activities were further validated by Western blot analysis for activation of EGFR and the downstream signaling in cancer cells."

Journal • Biosimilar • Non Small Cell Lung Cancer • Oncology

"Completely agree, look data for poziotinib, nazartinib, pyrotinib, TAS6417, TAK788, tarloxotinib, luminespib, WZ8040, WZ4002, and profound data around combos" (@AndresFCardonaZ)

Chemokine Receptor CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC (IASLC-WCLC 2019) - "Background: Activating EGFR mutations in NSCLC confer sensitivity to reversible EGFR TKIs, including gefitinib and erlotinib...The murine tumors driven by human EGFR exon19 deletion/T790M (TD) with acquired resistance to WZ4002 present mesenchymal phenotype and overexpress CXCR7... Taken together, we discovered that the CXCR7-CXCL12 signaling axis is necessary and sufficient for the maintenance of EGFR TKI resistance with mesenchymal phenotype and CXCR7 inhibition could significantly delay and prevent the emergence of acquired EGFR TKI resistance in EGFR mutant NSCLC."

T790M gatekeeper mutation emerges via de novo at the early stages of erlotinib treament in PC9 non-small cell lung cancer cells (AACR 2019) - "In addition, we show that the de novo T790M bearing erlotinib resistant PC9 cells are sensitive to the 3rd generation EGFR-targeted drug, WZ4002. Furthermore, GFP-based competition cell proliferation assays reveal that PC9 cells ectopically expressing EGFR mutant become more dominantly resistant to erlotinib than parental PC9 cells by acquiring T790M mutation. Taken together, we believe that our findings expand upon the previous notion of evolutionary paths of T790M development, providing an important clue to designing a therapeutic strategy to overcome drug resistance."

Monitoring activities of receptor tyrosine kinases using a universal adapter in genetically encoded split TEV assays. (PubMed, Cell Mol Life Sci) - "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."

Journal