TAK-285 / Takeda - LARVOL DELTA

Identification of novel HER2 ınhibitors: potential therapeutics for breast cancer. (PubMed, Discov Oncol) - "Among the tested compounds, axitinib, prunetin, and silymarin demonstrated strong HER2-binding affinities comparable to established inhibitors such as TAK-285 and lapatinib. Prunetin, with its lower toxicity and higher stability, presents a safer therapeutic option, whereas axitinib offers high binding affinity. These findings suggest that these compounds could help overcome resistance and side effects associated with current HER2-targeted therapies."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

A Promising Resveratrol Analogue Suppresses CSCs in Non-Small-Cell Lung Cancer via Inhibition of the ErbB2 Signaling Pathway. (PubMed, Chem Res Toxicol) - "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."

Journal • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD133 • CTNNB1 • POU5F1

Repurposing TAK-285 as An Antibacterial Agent against Multidrug-Resistant Staphylococcus aureus by Targeting Cell Membrane. (PubMed, Curr Microbiol) - "Conclusively, we repurposed TAK-285 as an antimicrobial with anti-biofilm properties against S. aureus by targeting cell membrane. This study provided strong evidence for the potential of TAK-285 as a promising antimicrobial agent against S. aureus."

Journal • Infectious Disease • HER-2

SYNTHESIS OF INDOLE-LINKED THIADIAZOLES AND THEIR ANTICANCER ACTION AGAINST TRIPLE-NEGATIVE BREAST CANCER. (PubMed, Chem Biodivers) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EGFR

Diosgenin and Monohydroxy Spirostanol from Prunus amygdalus var amara Seeds as Potential Suppressors of EGFR and HER2 Tyrosine Kinases: A Computational Approach. (PubMed, Pharmaceuticals (Basel)) - "The results showed that diosgenin and monohydroxy spirostanol exhibited binding energies comparable to those of the reference drugs, tak-285, and lapatinib. Additional in vivo and in vitro research are needed to certify these results and assess their efficacy and safety as cancer therapy agents. The experimental data reported and these results are in agreement."

Journal • Oncology • EGFR • HER-2

Development of new TAK-285 derivatives as potent EGFR/HER2 inhibitors possessing antiproliferative effects against 22RV1 and PC3 prostate carcinoma cell lines. (PubMed, J Enzyme Inhib Med Chem) - "Compounds 9a-h showed IC values in the range of 1.0-7.3 nM and 0.8-2.8 nM against PC3 and 22RV1 prostate carcinoma cell lines, respectively. Cell cycle analysis, apoptotic induction, molecular docking, dynamics, and MM-GBSA studies confirmed the plausible mechanism(s) of compound 9f as a potent EGFR/HER2 dual inhibitor with an effective antiproliferative action against prostate carcinoma."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

Identification of HER2 inhibitors from curcumin derivatives using combination of in silico screening and molecular dynamics simulation. (PubMed, J Biomol Struct Dyn) - "At the end, eight active curcumin derivatives were predicted as inhibitors of HER2 with high binding affinity and better interaction compared with the reference drug (Neratinib) but lower binding affinity compared with the co-crystalized ligand (TAK-285). This study revealed that curcumin derivatives especially (1E,6E)-1,8-bis(4-hydroxy-3-methoxyphenyl)octa-1,6-diene-3,5-dione and (1E,6E)-4-ethyl-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione were identified to demonstrate inhibitory activity against HER2 which is comparable to neratinib. Conclusively, the lead compounds require further in vitro and in vivo experimental validation for the discovery of new HER2 antagonists for breast cancer management.Communicated by Ramaswamy H. Sarma."

Journal • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor

Molecular docking of the pentapeptide derived from rice bran protein as anticancer agent inhibiting both receptor and non-receptor tyrosine kinases. (PubMed, J Biomol Struct Dyn) - "Erlotinib and TAK-285 were used as reference molecules. The strong interaction of the peptide with EGFR (from -9.24 to -9.75 kcal/mol) and the secondary mutant EGFR (from -9.28 to -9.64 kcal/mol) observed in most cancer recurrence cases indicates its good potential to overcome drug resistance in cancer therapy. In addition, the pharmacological properties of the investigated pentapeptides were revealed by in silico ADME (Absorption, Distribution, Metabolism, Excretion) and toxicity analysis.Communicated by Ramaswamy H. Sarma."

Journal • Oncology • EGFR

A drug-in-adhesive anti-onychomycotic nail patch: influence of drug and adhesive nature on drug release, ungual permeation, in vivo residence in human and anti-fungal efficacy. (PubMed, Int J Pharm) - "Comparison of the patches indicated greater residence of Duro-Tak 202A containing patches over those containing Duro-Tak 2852. Amorolfine HCl in Duro-Tak 202A based patch also showed antifungal efficacy in contrast to Duro-Tak 2852-based patch, and is particularly promising for further development as a potential toenail medicine, remaining almost fully adhered to toenails for at least two weeks."

Journal • Preclinical • Infectious Disease

Molecular recognition of tak-285 and lapatinib by inactive, active, and middle active-inactive HER2. (PubMed, J Mol Model) - "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."

Journal • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • HER-2

Short communication for targeting natural compounds against HER2 kinase domain as potential anticancer drugs applying pharmacophore based molecular modelling approaches- part 2. (PubMed, Comput Biol Chem) - "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."

Journal • Brain Cancer • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • EGFR • HER-2

Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients (Br J Cancer) - P1, N=26; TAK-285_101; 20 pts made up the dose escalation cohort & the remaining six pts were the repeated administration cohort; TAK-285 was well tolerated; Dose-limiting toxicities noted in two pts who received 400 mg b.i.d. were grade 3 increases in aminotransferases & grade 3 decreased appetite; MTD was determined to be 300 mg b.i.d; Absorption of TAK-285 was rapid after oral dosing, & plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d; A PR was observed for one pt with parotid cancer who received 300 mg b.i.d

P1 data • Oncology

Phase I study of TAK-285, an investigational HER2/EGFR inhibitor, in patients (pts) with advanced cancer: Updated results and assessment of human CSF distribution (ASCO 2011) - Abstract not available

Oncology

Systematic molecular profiling of inhibitor response to the clinical missense mutations of ErbB family kinases in human gastric cancer. (PubMed, J Mol Graph Model) - "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."

Clinical • Journal • EGFR • ERBB4 • HER-2

Structure-Based Drug Design Studies Toward the Discovery of Novel Chalcone Derivatives as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors. (PubMed, Molecules) - "Compound 1d showed to have a close binding energy with TAK-285 (-66.17 kcal/mol), which indicates a high chance for compound 1d to exhibit inhibitory activity, thus recommending to synthesis it to test its biological activity. It is anticipated that the findings reported here may provide very useful information for designing effective drugs for the treatment of EGFR-related cancer disease."

Journal

Molecular insight into the T798M gatekeeper mutation-caused acquired resistance to tyrosine kinase inhibitors in ErbB2-positive breast cancer. (PubMed, Comput Biol Chem) - "In the current study, the direct binding of three wild type-selective inhibitors (Lapatinib, AEE788 and TAK-285) and two wild type-sparing inhibitors (Staurosporine and Bosutinib) to the wild-type ErbB2 and its T798M mutant are investigated in detail by using rigorous computational analysis and binding affinity assay. The binding affinity of Staurosporine and Bosutinib to ErbB2 kinase domain is improved by 11.9-fold and 2.1-fold upon T798M mutation, respectively. Structural analysis reveals that a nonbonded network of S-π contact interactions (for Staurosporine) or an S-involving halogen bond (for Bosutinib) forms with the sulfide group of mutant Met798 residue."

Journal