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As a key guanine nucleotide exchange factor, SOS1 is an attractive therapeutic target for KRAS-driven colorectal cancer. In this study, based on the co-crystal structure of SOS1 in complex with BI-68BS, we developed a high-affinity fluorescent tracer TRR2 (KD = 0.134 μM), and established a robust fluorescence polarization assay for the profiling of SOS1 inhibitors. Subsequent structure-based optimization yielded a series of SOS1 inhibitors, among which SL43 emerged as the most promising candidate. SL43 demonstrated superior binding affinity to SOS1 (KD = 0.16 μM), potently disrupted the SOS1-KRASG12C interaction (IC50 = 13.0 nM) and broadly inhibited SOS1-mediated nucleotide exchange on multiple KRAS mutants (G12C, G12V and G12D; IC50 = 13.4-29.1 nM). Biologically, SL43 exhibited potent and selective antiproliferative activity against KRAS-mutant colorectal cancer cells (IC50 = 0.028-0.238 μM), achieving over 100-fold selectivity over KRAS wild-type cells. in Balb/c mice, SL43 displayed a favorable profile with a moderate half-life (T1/2 = 4.6 h) and high oral bioavailability (F = 56.8%). In an HCT116 xenograft model, oral administration of SL43 (20 and 40 mg/kg) also significantly suppressed tumor growth (TGI = 57.2% and 74.9%, respectively), outperforming MRTX0902 (60 mg/kg, TGI = 47.1%) with no observable systemic toxicity. In conclusion, SL43 represents a potent and orally bioavailable SOS1 inhibitor that effectively suppresses KRAS signaling and exerts strong antitumor efficacy, highlighting its potential as a promising candidate for KRAS-mutant colorectal cancer.

Gastric cancer remains a major cause of cancer mortality, and long-term control is still limited by recurrence, metastasis, and therapy resistance, creating a clear need for small molecules that act through noncanonical mechanisms. Lysosomes have become an attractive target because loss of lysosomal competence can translate into cytoplasmic vacuolization, impaired autophagic turnover, and ultimately cell death. Nur77 is a stress-responsive nuclear receptor implicated in tumor biology, but whether it can be pharmacologically harnessed to drive lysosome-centered vulnerability in gastric cancer has not been well established. Here, we designed and synthesized a series of 2-(6-(4-methoxyphenyl)-2-methylnicotinoyl)-N-substituted carboxamide/carbothioamide derivatives and identified compound 6K as the lead. 6K potently inhibited the growth of gastric cancer cells while showing low cytotoxicity toward normal gastric epithelial cells. In both HGC-27 and AGS cells, 6K reduced viability and clonogenic survival and rapidly induced prominent cytoplasmic vacuolization. In HGC-27 cells, 6K further caused LC3-II and p62 accumulation, loss of Lyso-Tracker signal, and partial rescue of vacuolization and colony formation by bafilomycin A1. 6K also induced apoptosis, supported by increased PARP cleavage, TUNEL positivity, and Annexin V/PI staining. Mechanistically, 6K directly bound the Nur77 ligand-binding domain, and Nur77 overexpression attenuated 6K-driven lysosomal perturbation and apoptotic signaling. In an HGC-27 xenograft model, 6K at 20 mg/kg significantly suppressed tumor growth without obvious histopathological injury to major organs. Collectively, these findings define 6K as a tractable Nur77 modulator that couples lysosomal dysfunction to apoptotic death in gastric cancer, providing a lead scaffold for lysosome-directed anticancer therapy.

In this work, a new series of N-arylmethylene/heterylmethylene-2-(4-oxo-1-phenyl-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)acetohydrazide 8a-l was synthesized via the condensation reaction of acetohydrazide 6 with various aromatic aldehydes 7a-l. The cytotoxic activity of these compounds was evaluated in vitro using against three human cancer cell lines: hepatocellular carcinoma (HepG2), prostate cancer (PC-3) and colorectal carcinoma (HCT-116). Among the synthesized series, compound 8g exhibited the highest potency, with IC₅₀ values of 3.93 μM, 9.56 μM, and 6.30 μM against HepG2, PC-3, and HCT-116, respectively, surpassing the reference drugs doxorubicin (4.50 μM against HepG2) and sorafenib (9.18 μM against HepG2). Mechanistically, 8g demonstrated strong inhibition of VEGFR2 (IC₅₀ = 0.38 μM), but it outperformed PD-L1 inhibition compared to Bavencio (IC₅₀ = 134.41 pg/mL and 217.74 pg/mL, respectively). In contrast, it enhanced INF-γ secretion in comparison to the reference drug. Cell cycle analysis revealed arrest at G0/G1with apoptosis induction at 29.41%. The apoptotic enzyme assay showed upregulation of BAX and Caspase-3, and downregulation of Bcl-2, confirming the activation of the intrinsic apoptotic pathway. In silico molecular docking and dynamic simulation assisted data strongly correlated with the experimental approach that compound 8g exerts multi-targeted anticancer activity via VEGFR2 and PD-L1 inhibition. In conclusion, 8g is a promising candidate recommended for further therapeutic development.

Cyclin-dependent kinase 2 (CDK2) and vascular endothelial growth factor receptor 2 (VEGFR2) are essential for the development of tumor angiogenesis and the cell cycle, respectively. Inhibiting both kinases at the same time has therefore become a sensible anticancer tactic. A number of unique hybrid compounds containing isatin-triazole and isatin-imidazole scaffolds were created and thoroughly described in an effort to find dual CDK2/VEGFR2 inhibitors. Compounds 5d, 5k, and 10 showed the strongest antiproliferative activity against breast (MCF7) and prostate (PC3) cancer cell lines among the produced derivatives. Notably, compound 10 showed the most inhibitory potency, with IC50 values of 0.058 μM for VEGFR2 and 0.789 μM for CDK2, respectively. These values are on par with or higher than those of the reference standards, roscovitine and sunitinib. Additionally, a biological study showed that compounds 5d and 5 k had negligible off-target toxicity and were selectively lethal to cancer cells compared to normal HaCaT keratinocytes. Furthermore, cell cycle studies revealed that compound 5d produced S-phase arrest, whereas compounds 5 k and 10 mostly caused G-phase arrest, in line with their kinase inhibition profiles. Additionally, the potent analogues 5d and 10 substantially decreased colony formation and tumoral cell migration. Molecular docking and dynamics simulations helped to clarify the possible binding interactions inside the ATP-binding sites of CDK2 and VEGFR2, confirming the dual-binding mechanism that underlies their potent effects. According to all of these findings, compound 10 is a potential dual CDK2/VEGFR2 inhibitor that offers a helpful foundation for the development and optimization of future multitarget anticancer agents.

We previously described the discovery of carbamate-derived small molecules as potent and selective lysophosphatidic acid receptor 1 (LPA1) antagonists. To further expand the library of LPA1 antagonists and potentially enhance their stability and potency, a urea moiety was introduced in replacement of the carbamate group and a series of LPA1 antagonists based on a urea scaffold were synthesized and evaluated. Within this series, several compounds exhibited potent LPA1 antagonism. Notably, compound 5f emerged as one of the most potent, with an IC50 of 215.2 nM in the cAMP assay and 7.9 nM in the calcium mobilization assay. Compound 5f demonstrated the ability to block LPA-induced cell migration and invasion in the triple-negative breast cancer cell line MDA-MB-231. These findings support further in vivo evaluation of compound 5f as a potential therapeutic agent targeting LPA1. The development of these urea-derived LPA1 antagonists in this study has expanded the repertoire of LPA1 antagonists and holds potential for the development of a novel therapy for metastatic triple-negative breast cancer.

Cancer remains a formidable disease with significantly high mortality rates worldwide. Herein, we attempted to design and evaluate a new class of VEGFR-2 and HDAC dual acting anticancer agents. The rationale was based on the defined pharmacophores of VEGFR-2 inhibitors and HDAC inhibitors, as we synthesized new quinazolinone based-benzamides that bring together both features. The new candidates showed considerable in vitro activity against MDA-MB-231 and HCT-116 cancer cell lines, in particular 4-hydroxyphenylbenzamide derivative of 3-ethylquinazolinone 7d, which revealed IC50 of 5.39 ± 0.08 μM and 4.11 ± 0.13 μM, in comparison with IC50 of 29.13 ± 2.28 μM and 33.50 ± 2.43 μM, obtained for the reference drug, sorafenib, respectively. So, 7d was approximately 5.4-fold and 8.2-fold more potent than sorafenib against the aforementioned cell lines, respectively. Additionally, 7d had far better selectivity to cancer cells, showing selectivity indices of 5.11 and 6.68, compared to 1.73 and 1.51 recorded for sorafenib against the two cancer cell lines, respectively. Furthermore, it also showed a significant dual inhibition of VEGFR-2 and HDAC-2. It showed IC50 of 0.407 ± 0.015 μM against VEGFR-2, revealing approximately half the potency of sorafenib. Whereas, It was approximately 1.26 times more potent than vorinostat against HDAC-2, demonstrating an IC50 of 0.363 ± 0.013 μM. Furthermore, 7a was proven to be an apoptotic inducer to HCT-116 cells, increasing the apoptosis rate by 10-folds and causing cell cycle arrest at the G1 phase. Meanwhile, the expression level of caspase-3 and the BAX/BCL-2 ratio were markedly elevated in HCT-116 cells treated with 7d. Finally, the presented data are reliable for developing dual VEGFR-2 and HDAC inhibitors as anticancer drugs and reveal lead molecules for such purpose.

A library of new methoxyquinazoline sulfonamide derivatives was synthesized through two main structural modifications: either by introducing methoxy groups at the quinazoline ring, or S-alkylation with acetamide moieties bearing differently substituted aromatic groups to explore the structure-activity relationship. The synthesized compounds were assessed for their cytotoxic effects against A549, MDA-MB-231 and HepG-2 cancer cell lines, as well as WI-38 and MCF-10A normal cell lines. Among these derivatives, the trimethoxy-substituted quinazolines 9a-c showed the highest cytotoxic potency, with compound 9a emerging as the lead candidate. Compound 9a displayed strong inhibitory activity against VEGFR-2, with an IC50 value of 0.23 ± 0.03 μM, comparable to that of sorafenib. It inhibited HepG-2 cell migration in a wound healing assay, which correlated with a reduction in Akt phosphorylation (p-Akt), suggesting its potential to modulate VEGFR-2-mediated signaling pathways involved in angiogenesis. Compound 9a induced apoptosis, evidenced by caspase-3 activation, upregulation of Bax, downregulation of Bcl-2 and a marked increase in Bax/Bcl-2 ratio. Cell cycle analysis demonstrated G2/M phase arrest, supporting its antiproliferative activity. It also revealed enhanced radiation-induced cytotoxicity when combined with a single 8 Gy dose of gamma radiation. Docking within the VEGFR-2 active site supported the biological findings by revealing promising binding interactions. Besides, ADME analysis supports the design strategy and suggests that these derivatives possess promising pharmacokinetic properties.

The C797S mutation in epidermal growth factor receptor (EGFR) is a major mechanism of resistance to third-generation tyrosine kinase inhibitors (TKIs), such as Osimertinib, in non-small cell lung cancer (NSCLC), creating an urgent need for effective therapeutic strategies. To address this challenge, we designed the structure-guided optimization of a 2-aryl-4-aminoquinazoline scaffold, leading to the discovery of a potent fourth-generation EGFR inhibitor, compound 6g. The design focused on introducing flexible nitrogen-rich side chains to enable effective non-covalent interaction with the mutant Ser797 residue. Compound 6g exhibited superior activity against EGFRDel19/T790M/C797S with an enzymatic IC50 of 0.056 μM and potently inhibited the proliferation of resistant PC-9 cells (IC50 = 0.143 μM), outperforming the parent lead Angew-1 and Osimertinib by 6-fold and 16-fold, respectively. Further biological evaluation revealed that 6g effectively suppressed proliferation, migration, and induced apoptosis in Osimertinib-resistant cells, concomitant with the inhibition of EGFR and its downstream AKT/MAPK signaling pathways. Favorable pharmacokinetic properties were observed in rats, with an absolute oral bioavailability of 22.33% and a high safety margin (selectivity index >500 in normal human lung epithelial BEAS-2B cells). In a PC-9Del19/T790M/C797S xenograft model, 6g achieved significant dose-dependent tumor growth inhibition (TGI: 47.3% at 5 mg/kg; 64.2% at 10 mg/kg), markedly surpassing Osimertinib (TGI: 16.07% at 10 mg/kg), with no observed significant toxicity. These results establish 6g as a promising fourth-generation EGFR-TKI candidate with potent activity, favorable pharmacokinetics, and a high safety profile, offering a potential therapeutic strategy against Osimertinib resistance driven by the C797S mutation.

A series of novel benzimidazole-based thioamide derivatives were designed, synthesized, and evaluated for their anticancer potential, supported by EGFR-targeted molecular docking studies. The synthetic strategy involved a base-mediated nucleophilic substitution reaction between 1-(substitutedphenyl)-2-((5-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)thio)ethan-1-one intermediate (1) and brominated nitrobenzyl derivative (2), enabling efficient CC bond formation at the C5 position of the benzimidazole ring. Reaction parameters were systematically optimized, including solvent, base, and temperature, wherein acetonitrile as solvent and potassium carbonate as base under reflux conditions afforded the best yields. Under optimized conditions, a library of ten derivatives was synthesized and fully characterized using NMR spectroscopy. The synthesized compounds were evaluated for in vitro cytotoxic activity against three human cancer cell lines: MCF7 (breast), A-549 (lung), and HEP-G2 (liver). Several derivatives exhibited promising anticancer activity, with compound 6-8b emerging as the most potent, displaying IC₅₀ values of 3.70 μM against A-549 and 5.38 μM against HEP-G2 cells. Molecular docking studies against the T790M-mutated EGFR kinase domain (PDB ID: 2JIV) revealed favorable binding interactions, superior docking scores, and binding energies compared to the reference inhibitor Neratinib. ADME predictions were made using Qikprop. These derivatives may represent a preliminary lead scaffold warranting further mechanistic validation and structural optimization; however, experimental confirmation of EGFR target engagement is required before definitive anticancer claims can be made.

Histone deacetylases (HDACs) serve as crucial epigenetic modulators implicated in tumorigenesis. Consequently, targeting HDACs is considered an emerging strategy in cancer therapy. Leveraging scaffold hopping and structural optimization strategies, we developed fifteen indole-based derivatives utilizing vorinostat (SAHA) and entinostat as lead compounds. The synthesized compounds were evaluated against HDAC1 and HDAC6 isoforms, revealing that all the hydroxamate derivatives (15a-c, 16a, 16b, 17, and 18) displayed potent HDAC1/6 inhibitory activity with preferential inhibition of HDAC6, exhibiting IC50 values in the low nanomolar range (1-12 nM) against HDAC6, surpassing SAHA by 2- to 16-fold. In contrast, the benzamide derivatives (23a-c, 24, 25, and 26) exhibited notable preferential inhibition of HDAC1 over HDAC6. Furthermore, HDAC isoform selectivity profiling revealed that 18 preferentially inhibited HDAC6 over class I isoforms, whereas 23c showed a preference for HDAC1 inhibition. Comparative molecular docking of 18 and SAHA provided supportive insight consistent with the observed higher potency of 18. Intriguingly, the preliminary screening against the NCI-60 panel at 10 μM indicated ten compounds with pronounced antiproliferative activity, warranting their progression to subsequent concentration-response screening. Notably, the benzamide series exhibited potent cytotoxicity with GI50 values in the nanomolar to low micromolar range across the entire NCI-60 panel. Mechanistic investigations of representative hydroxamate and benzamide derivatives corroborated their marked antiproliferative effects in HCT-116 cancer cells and manifested a favorable safety profile against the normal fibroblasts (WI-38). Altogether, these findings underscore the therapeutic potential of the identified potent compounds for combating cancer via HDAC1/6 inhibition.