Tesevatinib

Tesevatinib (KD019, XL647) is an experimental drug proposed for use in kidney cancer and polycystic kidney disease. The drug was first developed by Exelixis, Inc.[1] and was later acquired by Kadmon Corporation. Tesevatinib binds to and inhibits several tyrosine receptor kinases that play major roles in tumor cell proliferation and tumor vascularization, including epidermal growth factor receptor (EGFR; ERBB1), epidermal growth factor receptor 2 (HER2; ERBB2), vascular endothelial growth factor receptor (VEGFR), and ephrin B4 (EphB4).[2]

Tesevatinib

Clinical data
Routes of administration	Oral administration (tablets)
Pharmacokinetic data
Elimination half-life	50–70 hours
Identifiers
IUPAC name N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-{[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methoxy}quinazolin-4-amine
CAS Number	781613-23-8
PubChem CID	10458325
DrugBank	DB11973
ChemSpider	32699556
UNII	F6XM2TN5A1
KEGG	D11772
Chemical and physical data
Formula	C24H25Cl2FN4O2
Molar mass	491.39 g·mol^−1
3D model (JSmol)	Interactive image
SMILES CN1C[C@H]2C[C@H](C[C@H]2C1)COc3cc4c(cc3OC)c(ncn4)Nc5ccc(c(c5F)Cl)Cl
InChI InChI=1S/C24H25Cl2FN4O2/c1-31-9-14-5-13(6-15(14)10-31)11-33-21-8-19-16(7-20(21)32-2)24(29-12-28-19)30-18-4-3-17(25)22(26)23(18)27/h3-4,7-8,12-15H,5-6,9-11H2,1-2H3,(H,28,29,30)/t13-,14-,15+ Key:HVXKQKFEHMGHSL-QKDCVEJESA-N

The drug activity was initially studied in non-small cell lung cancer.[3] In a 2007 pre-clinical study with xenograft tumors of an erlotinib-resistant cell line tesevatinib substantially inhibited the growth of these tumors.[4] In polycystic kidney disease, a histological study of the drug effects and toxicity in rats and mice was published in July 2017.[5]

As of March 2019 the drug was in Phase II clinical trials for the treatment of polycystic kidney disease in adults and children.[6]

References

1. Gendreau SB, Ventura R, Keast P, Laird AD, Yakes FM, Zhang W, et al. (June 2007). "Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647". Clinical Cancer Research. 13 (12): 3713–23. doi:10.1158/1078-0432.CCR-06-2590. PMID 17575237. Retrieved 30 October 2017.
2. "Substance Name: Tesevatinib [USAN:INN]". US National Library of Medicine. Retrieved 30 October 2017. This article incorporates text from the United States National Library of Medicine, which is in the public domain.
3. Carrizosa DR, Mileham KF, Haggstrom DE (May 2013). "New targets and new mechanisms in lung cancer". Oncology. Williston Park, N.Y. 27 (5): 396–404. PMID 25184262.
4. Gendreau SB, Ventura R, Keast P, Laird AD, Yakes FM, Zhang W, et al. (June 2007). "Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647". Clinical Cancer Research. 13 (12): 3713–23. doi:10.1158/1078-0432.CCR-06-2590. PMID 17575237.
5. Sweeney WE, Frost P, Avner ED (July 2017). "Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease". World Journal of Nephrology. 6 (4): 188–200. doi:10.5527/wjn.v6.i4.188. PMC 5500456. PMID 28729967.
6. Clinical trial number NCT03203642 for "Study of the Efficacy and Safety of Tesevatinib in Subjects With ADPKD" at ClinicalTrials.gov