Description
Ortataxel is a novel second-generation taxane, with potent growth inhibitory activity against human cell lines that express P-glycoprotein 170. Compared to paclitaxel and docetaxel, it is 20-30 times more potent as a growth inhibitory agent against human breast and colon tumor cell lines expressing P-gp 170. Ortataxel is also active in NSCL tumor xenografts.
Definition
Ortataxel is a semisynthetic, second-generation taxane derivative with potential antineoplastic activity. Ortataxel binds to and stabilizes tubulin molecules, thereby interfering with the dynamics of microtubule assembly/disassembly. This results in the inhibition of cell division and cellular proliferation. As it represents a poor substrate for P-glycoprotein (P-gp), multi-drug resistance protein (MRP-1) and breast cancer resistance protein (BCRP) mediated efflux, ortataxel modulates multi-drug resistance mechanisms and may be useful for treating multi-drug resistant tumors that express Pgp, MRP-1 and BCRP.
Biological Activity
bay-598 is a aminopyrazoline-based in-vivo probe for smyd2.smyd2 is a catalytic set domain containing protein methyltransferase to monomethylate lysine residues on histone and nonhistone proteins. the overexpression of smyd2 has been found in cancer cell lines and also in various cancer patients.
in vitro
previous data suggest that bay-598 is a peptide-competitive, sam-uncompetitive inhibitor of smyd2 methyltransferase activity, binding to the smyd2 sam substrate complex. bay-598 was tested on a panel of 32 additional methyltransferases, and the results showed that bay-598 displayed >100-fold selectivity for smyd2, with very weak activity for the closest related methyltransferase smyd3. though bay-598 proved to be active for both smyd2 inhibition and par1 antagonism, there was still a greater than 50-fold selectivity for smyd2 relative to par1 [1].
in vivo
in animal study, mice bearing subcutaneous tumor xenografts were orally treated with 10, 30, 70, or 100 mg/kg bay-598 once daily for 3 days. results showed that bay-598 could significantly reduce the methylation with doses starting from 30 mg/kg, with most significant effects in the 100 mg/kg group. treatment with 10 mg/kg bay-598 showed no significant effect on the methylation level, although the exposure at 10 mg/kg was close to the cellular ic50 for about 9 h, indicating an even higher exposure as the ic50 to achieve in-vivo effects [1].
References
[1] ERIK EGGERT. Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2[J]. Journal of Medicinal Chemistry, 2016, 59 10: 4578-4600. DOI:
10.1021/acs.jmedchem.5b01890.
[2] Ortataxel[J]. Definitions, 2020, 97 1. DOI:
10.32388/02e3an.
[3] HANS MINDERMAN. Broad-spectrum modulation of ATP-binding cassette transport proteins by the taxane derivatives ortataxel (IDN-5109, BAY 59-8862) and tRA96023.[J]. Cancer Chemotherapy and Pharmacology, 2004, 53 5: 363-369. DOI:
10.1007/s00280-003-0745-2.
[4] J. GURTLER. An uncontrolled phase II study evaluating anti-tumor efficacy and safety of ortataxel (BAY 59–8862) in patients with taxane-resistant non-small cell lung cancer[J]. Journal of Clinical Oncology, 2004, 22 1: 7136-7136. DOI:
10.1200/JCO.2004.22.90140.7136.
