TAK-285

• CAT Number: I005244
• CAS Number: 871026-44-7
• Molecular Formula: C26H25ClF3N5O3
• Molecular Weight: 547.96
• Purity: ≥95%
• Synonyms: N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3-methylbutanamide
• Target: HER2
• Solubility: DMSO 110 mg/ml
• Storage: 3 years -20C powder
• IC50: 17/23 nM (HER2/1) [1]

TAK-285 is a novel dual HER2 and EGFR(HER1) inhibitor with IC50 of 17 nM and 23 nM, >10-fold selectivity for HER1/2 than HER4, less potent to MEK1/5, c-Met, Aurora B, Lck, CSK etc.IC50 value: 17/23 nM (HER2/1) [1]Target: HER1/2in vitro: MEK1, MEK5, c-Met, Aurora B, Lck, CSK, and Lyn B with IC50 of 1.1 μM, 5.7 μM, 4.2 μM, 1.7 μM, 2.4 μM, 4.7 μM, and 5.2 μM, respectively, and displays no activity against other kinases with IC50 of >10 μM. TAK-285 shows significant growth inhibitory activity against BT-474 cells (HER2-overexpressing human breast cancer cell line) with GI50 of 17 nM [1]. Compared with SYR127063 a potent inhibitor of HER2, TAK-285 displays similar in vitro potency against HER2 and EGFR. Compared with the full cytoplasmic domains of the wild-type proteins, the mutations and shortened boundaries used for structure determination of HER2-KD and EGFR-KD do not significantly change the inhibitory activity (IC50) of TAK-285. TAK-285 binds to the inactive conformation of EGFR, and shows a similar binding mode with lapatinib in the active site [2].in vivo: The oral bioavailability of TAK-285 is 97.7% in rats and 72.2% in mice at a dose of 50 mg/kg. Oral administration of TAK-285 at 100 mg/kg twice daily for 14 days displays significant antitumor efficacy in the HER2-overexpressing BT-474 tumor xenograft mouse model with tumor/control (T/C) ratio of 29%, without affecting body weight. Similar to the BT-474 model, TAK-285 exhibits dose-dependent tumor growth inhibition of 4-1ST (HER2-overexpressing human gastric cancer tumor) xenografts in mice, with T/C of 44% and 11% at doses of 50 mg/kg and 100 mg/kg, twice daily, respectively, without significant body weight loss in mice [1]. After oral administration of TAK-285, a significant amount of TAK-285 is present in the brain of rats in pharmacologically active, unbound form (approximately 20% of its free plasma level), indicating that TAK-285 has a potential in the therapy of CNS malignancies/metastases [3].

Reference

1:HER2 and HER3 cooperatively regulate cancer cell growth and determine sensitivity to the novel investigational EGFR/HER2 kinase inhibitor TAK-285. Takagi S, Banno H, Hayashi A, Tamura T, Ishikawa T, Ohta Y.Oncoscience. 2014 Mar 24;1(3):196-204. eCollection 2014. PMID: 25594012 Free PMC Article2:Antitumor Activity of TAK-285, an Investigational, Non-Pgp Substrate HER2/EGFR Kinase Inhibitor, in Cultured Tumor Cells, Mouse and Rat Xenograft Tumors, and in an HER2-Positive Brain Metastasis Model. Nakayama A, Takagi S, Yusa T, Yaguchi M, Hayashi A, Tamura T, Kawakita Y, Ishikawa T, Ohta Y.J Cancer. 2013 Aug 16;4(7):557-65. doi: 10.7150/jca.6689. eCollection 2013. PMID: 23983820 Free PMC Article3:Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2. LoRusso P, Venkatakrishnan K, Chiorean EG, Noe D, Wu JT, Sankoh S, Corvez M, Sausville EA.Invest New Drugs. 2014 Feb;32(1):160-70. doi: 10.1007/s10637-013-9988-x. Epub 2013 Jul 2. PMID: 23817974 Free PMC Article4:Verification of brain penetration of the unbound fraction of a novel HER2/EGFR dual kinase inhibitor (TAK-285) by microdialysis in rats. Erdo F, Gordon J, Wu JT, Sziráki I.Brain Res Bull. 2012 Mar 10;87(4-5):413-9. doi: 10.1016/j.brainresbull.2012.01.002. Epub 2012 Jan 9. PMID: 22245027 5:Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients. Doi T, Takiuchi H, Ohtsu A, Fuse N, Goto M, Yoshida M, Dote N, Kuze Y, Jinno F, Fujimoto M, Takubo T, Nakayama N, Tsutsumi R.Br J Cancer. 2012 Feb 14;106(4):666-72. doi: 10.1038/bjc.2011.590. Epub 2012 Jan 12. PMID: 22240796 Free PMC Article