TAK-285

Additionally, molecular docking and bioinformatic analysis suggest ErbB2 as a potential target of the compound with a strong binding affinity (-6.709 kcal/mol) compared to the reference compound TAK-285 (-5.563 kcal/mol)...In conclusion, we highlight the novel resveratrol derivative YI-12 for its ability to inhibit CSCs through the ErbB2 signaling pathway. This compound represents a promising structure that should be further developed for potential use in anticancer therapy.

With a high docking score (-9.9 to -8.7 kcal/mol), the indole hybrids display significant binding propensity comparable to the co-crystallized ligand TAK-285 and occupy a similar strategic position in the active domain of the designated receptor...The indole hybrids show near-appropriate pharmacokinetic efficacy and bioavailability in the in-silico studies, indicating their candidacy for potential drug usage. Promising in-vitro anticancer action and binding interfaces project indole conjugates as potential leads in addressing the TNBC dilemma.

Structural and energetic studies revealed that tak-285 binds with a greater affinity than lapatinib to active and intermediate active-inactive forms of HER2. This is in accordance with experimental findings that showed the tak-285 inhibitor has increased activity relative to lapatinib in breast cancer cell lines.

Accordingly, the pharmacophore modelling approaches were adapted to identify two prospective compounds and were docked against the target 3RCD that is complexed with TAK-285 a known dual inhibitor...The Hit compounds have demonstrated a potential to penetrate the blood brain barrier thereby enriching their therapeutics towards breast cancer brain metastasis. Taken together, our findings propose two candidate compounds as EGFR/HER2 inhibitors that might serve as novel chemical spaces for designing and developing new inhibitors.

Two ErbB2 mutations, namely V777L and T862A, are predicted to cause effective resistance on inhibitors TAK285 and Lapatinib, respectively. Kinase assays consistently observe that the mutations can reduce inhibitor activity by 4.9-fold and 2.4-fold, with IC changing from 29 to 16 nM (wild type) to 83 and 39 nM (mutant) for TAK285 and Lapatinib, respectively.