Current clinical therapeutics against non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (EGFRExon20Ins) mutations yield limited responses particularly against brain metastases; therefore, there is a need for an effective tyrosine kinase inhibitor (TKI). AZ14289671 is an oral, potent, irreversible, selective, and blood-brain barrier penetrant TKI targeting EGFRExon20Ins mutations while sparing wild-type (WT) EGFR. Preclinical assessments using cell lines, cell line-derived xenograft, and patient-derived xenograft models harboring EGFRExon20Ins demonstrate that AZ14289671 exhibits strong signaling pathway inhibition and highly sustained tumor regression against multiple EGFRExon20Ins, whereas its activity against WT is minimal. Additionally, AZ14289671 can cross the blood-brain barrier. This has the potential to improve outcomes of NSCLC patients with EGFRExon20Ins.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.

Two series of quinoline-thiazole and quinoline-thiazolidinone hybrids were designed, synthesized, and evaluated for their in vitro antitumor activity on MCF-7 breast cancer cell line. In comparison with lapatinib (IC50  = 4.69 µM), compounds 4b and 6b exhibited the best antiproliferative activity with IC50 values of 33.19 and 5.35 µM, respectively. Although compound 6b showed higher cytotoxicity, compound 4b exhibited better inhibitory activity toward the epidermal growth factor receptor (EGFR) pathway than compound 6b as represented by the significant reduction in the EGFR kinase activity and the levels of phosho-EGFR and phosho-AKT when compared to lapatinib as a reference standard. Moreover, compound 4b was capable of down-regulating the anti-apoptotic genes Bcl-2 and survivin and up-regulating the level of the pro-apoptotic gene BAX. Molecular modeling study was carried out to predict the binding interactions of both compounds into the target kinase. Finally, the physicochemical properties were investigated in silico as well.
© 2021 John Wiley & Sons.

Oncogenic forms of KRAS proteins are known to be drivers of pancreatic, colorectal, and lung cancers. The goal of this study is to identify chemical leads that inhibit oncogenic KRAS signaling. We first developed an isogenic panel of mouse embryonic fibroblast (MEF) cell lines that carry wild-type RAS, oncogenic KRAS, and oncogenic BRAF. We validated these cell lines by screening against a tool compound library of 1402 annotated inhibitors in an adenosine triphosphate (ATP)-based cell viability assay. Subsequently, this MEF panel was used to conduct a high-throughput phenotypic screen in a cell viability assay with a proprietary compound library. All 126 compounds that exhibited a selective activity against mutant KRAS were selected and prioritized based on their activities in secondary assays. Finally, five chemical clusters were chosen. They had specific activity against SW620 and LS513 over Colo320 colorectal cancer cell lines. In addition, they had no effects on BRAFV600E, MEK1, extracellular signal-regulated kinase 2 (ERK2), phosphoinositide 3-kinase alpha (PI3Kα), AKT1, or mammalian target of rapamycin (mTOR) as tested in in vitro enzymatic activity assays. Biophysical assays demonstrated that these compounds did not bind directly to KRAS. We further identified the mechanism of action and showed that three of them have CDK9 inhibitory activity. In conclusion, we have developed and validated an isogenic MEF panel that was used successfully to identify RAS oncogenic or wild-type allele-specific vulnerabilities. Furthermore, we identified sensitivity of oncogenic KRAS-expressing cells to CDK9 inhibitors, which warrants future studies of treating KRAS-driven cancers with CDK9 inhibitors.

Derailed transmembrane receptor trafficking could be a hallmark of tumorigenesis and increased tumor invasiveness, but receptor dynamics have not been used to differentiate metastatic cancer cells from less invasive ones. Using single-particle tracking techniques, we  developed a phenotyping asssay named Transmembrane Receptor Dynamics (TReD), studied the dynamics of epidermal growth factor receptor (EGFR) in seven breast epithelial cell lines and developed a phenotyping assay named Transmembrane Receptor Dynamics (TReD). Here we show a clear evidence that increased EGFR diffusivity and enlarged EGFR confinement size in the plasma membrane (PM) are correlated with the enhanced metastatic potential in these cell lines. By comparing the TReD results with the gene expression profiles, we found a clear negative correlation between the EGFR diffusivities and the breast cancer luminal differentiation scores (r = -0.75). Upon the induction of epithelial-mesenchymal transition (EMT), EGFR diffusivity significantly increased for the non-tumorigenic MCF10A (99%) and the non-invasive MCF7 (56%) cells, but not for the highly metastatic MDA-MB-231 cell. We believe that the reorganization of actin filaments during EMT modified the PM structures, causing the receptor dynamics to change. TReD can thus serve as a new biophysical marker to probe the metastatic potential of cancer cells and even to monitor the transition of metastasis.