Telatinib (BAY 57-9352)

Telatinib (BAY 57-9352) is a selective inhibitor of VEGFR2, VEGFR3, c-Kit and PDGFRα with IC50 value of 6 nM, 4 nM, 1 nM and 15 nM, respectively [1].

Vascular endothelial growth factor receptor (VEGFR) is the receptor of VEGF and plays an important role in stimulating vasculogenesis and angiogenesis. Platelet-derived growth factor (PDGF) is a member of growth factors and involves in blood vessel formation. C-Kit is the receptor of a growth factor. Many studies have shown that abnormal of VEGFR, c-Kit and PDGFR are correlated with a variety of tumors [1, 2, 3].

Telatinib is a potent VEGFR2/3, c-Kit and PDGFRα inhibitor. When tested with a panel of tumor cell lines (MDA-MB-231 breast caicinoma, Colo-205 colon carcinoma, DLD-1 colon carcinoma and H460 non-small cell lung carcinoma), Telatinib treatment exhibited inhibition on VEGFR-2 autophosphorylation and PDGF-βwhich involved in the angiogenic process [2].

Telatinib has been used in clinical trails to a variety of cancers treatment and has achieved promising results [2-4].

It is also reported that Telatinib restores tumor cells sensitivity to anticancer drugs and significantly reduced cellular viability by inhibiting ABCG2 expression [3].

References:
[1].  Steeghs, N., et al., Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res, 2008. 14(11): p. 3470-6.
[2].  Strumberg, D., et al., Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours. Br J Cancer, 2008. 99(10): p. 1579-85.
[3].  Sodani, K., et al., Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo. Biochem Pharmacol, 2014. 89(1): p. 52-61.
[4].   Eskens, F.A., et al., Phase I dose escalation study of telatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet-derived growth factor receptor beta, and c-Kit, in patients with advanced or metastatic solid tumors. J Clin Oncol, 2009. 27(25): p. 4169-76.

Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours.[Pubmed:19002179]

Br J Cancer. 2008 Nov 18;99(10):1579-85.

Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor beta tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median t(max) of 3 hours or less. Geometric mean C(max) and AUC(0-12) increased in a less than dose-proportional manner and plateaued in the 900-1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC(0-12) of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose.

Phase I study of telatinib (BAY 57-9352): analysis of safety, pharmacokinetics, tumor efficacy, and biomarkers in patients with colorectal cancer.[Pubmed:21801343]

Vasc Cell. 2011 Jul 29;3:16.

BACKGROUND: Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor beta tyrosine kinases. METHODS: In this multicenter phase I dose-escalation study including a phase II like expansion part, 39 patients with refractory colorectal cancer (CRC) were enrolled into 14 days on / 7 days off in repeating cycles of 28 days (n = 11) or continuous dosing groups (n = 28) to receive >/= 600 mg telatinib twice-daily (bid). RESULTS: Hypertension (28%) and diarrhoea (15%) were the most frequent study drug-related adverse events of CTC grade 3. In this population, no clear relationship between telatinib dose and individual Cmax and AUC was apparent in the 600 mg bid to 1500 mg bid dose range. No partial remission according to RECIST was reached, but 41% of the patients reached some tumour shrinkage during treatment. Tumour blood flow measured by dynamic contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing telatinib AUC(0-12). CONCLUSION: Telatinib treatment was well tolerated. The observed single agent antitumor activity in heavily pretreated CRC patients was limited. Pharmacodynamic results are suggestive for the biological activity of telatinib justifying a further evaluation of telatinib bid in combination with standard chemotherapy regimens in CRC patients.

Telatinib (Bay 57-9352) is an orally active, small molecule inhibitor of VEGFR2, VEGFR3, PDGFα, and c-Kit with IC50s of 6, 4, 15 and 1 nM, respectively.

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