KDR (Kinase insert domain receptor)

Nano-formulated curcumin demonstrates strong, multi-target anticancer activity by blocking cell growth and angiogenesis while promoting apoptosis. These findings support its potential as a safe and effective therapeutic option for breast cancer.

In addition, molecules 7c, 8b, 7e, 7b and 8c, with IC50 values of 0.25, 0.32, 0.35, 0.45 and 0.50 µM, respectively, displayed very good EGFRT790M inhibition. Furthermore, molecules 7c, 7e and 8b exhibited excellent ADMET profile compared to sorafenib and erlotinib.

Sorafenib is a tyrosine kinase inhibitor (TKI) used to treat hepatocellular carcinoma (HCC), but this drug causes clinically significant toxicities in approximately 50% of patients...In addition, 6e attenuated the growth of HepG2 xenograft tumours in mice at a dose of 1 mg/kg for 3 weeks. Based on these results, this pyrimidine derivative could be an interesting compound for the design of new agents against HCC.

Importantly, depletion of TipECs using the first-in-class monoclonal antibodies against a highly conserved WQF-motif of Doppel robustly decreased the growth of tumors by selectively downregulating VEGFR2+ TipECs but not StalkECs. These findings position Doppel as a tumor TipEC-specific, druggable target that may offer a new avenue to enhance and refine anti-angiogenic therapies in cancer treatment.

EGFR 19Del and 21L858R mutations are associated with distinct expression patterns of VEGFR1 and CD34, which may underlie differential responses to anti-angiogenic therapy and inform future combination treatment strategies.

Significant proportions of fragmented DNA (25.67%, 28.81%, and 32.56%) were identified by 7, 9 and 11, respectively. Compound 7 showed mild inhibition against VEGFR-2 compared to sorafenib, the standard inhibitor.

Few FDA approved drugs (such as Sorafenib, Sunitinib, Nintedanib and Cabotanzinib), which target VEGFRs, however, a significant issue with the monotherapy of these agents is drug resistance. Finally, in silico molecular docking studies on VEGFR-2 (PDB ID 3VHE) revealed that compounds 5d, 5j, and 5q showed encouraging inhibition constants (68.5-154.92 nM) and binding energies (-9.29 to -9.77 kcal/mol) compared to Sunitinib (inhibition constant = 248.72 nM) and binding energy = -9.01 kcal/mol). Specifically, compounds 5d and 5j established an H-bond with the ASP1046 residue, similar to the standard drug Sunitinib.

Cytotoxic effects on A549 cell lines, compared to sorafenib (4.04 μM) and erlotinib (5.49 μM), showed that compounds 4, 5, 6, 7, 8, 10 and 11 with the IC50 values of 5.50-8.00 μM exhibited very high activities. Molecular docking was carried out for all derivatives to show their binding affinities and orientations inside the active sites of VEGFR-2 and EGFRT790M receptors to support the in vitro results. The data obtained from docking is highly matched with that obtained from biological testing.

DC101-mediated vascular normalization beneficially remodels the GBM TME and creates a quiescent platform for supporting future FUS-based therapeutic delivery. This combinatorial strategy offers a promising approach to overcoming BBB-related barriers in glioma treatment.

The 200 ns molecular dynamics (MD) simulations confirmed the stability of the 4ASD-6b complex with enhanced flexibility compared to sorafenib. Collectively, these findings establish benzothiazole, benzimidazole, and quinoline-based urea hybrids as promising leads with enhanced multikinase selectivity and reduced toxicity compared to existing inhibitors, offering strong therapeutic potential in angiogenesis-driven cancers.

Among the series, compounds 6b, 6d, and 6g demonstrated exceptional growth-inhibitory (GI) potency, achieving GI% values of 80.32%, 79.24%, and 86.40%, respectively-substantially outperforming doxorubicin (61.49%)...Several other analogues, including 6d, 6e, 6i, and 6j, also displayed potent cytotoxicity (IC50 < 10 µM), highlighting the broader therapeutic relevance of this scaffold. Collectively, these data position 6g as a compelling multi-target anticancer lead that integrates apoptosis induction, cell-cycle regulation, and angiogenesis suppression-supporting its potential for development as a next-generation broad-spectrum anticancer agent.

Also underscored are the existence of commercially available drugs and patented compounds, as well as translational candidates featuring the 2-aminobenzothiazole pharmacophore. The paper emphasises the dual mechanistic targetability of 2-aminobenzothiazole derivatives as valuable lead compounds targeting both kinases and other targets in an innovative manner aimed at future development of targeted anti-cancer therapies.