On November 20, 2014 Deciphera Pharmaceuticals reported the presentation of preclinical data which demonstrated that altiratinib (DCC-2701) provided balanced inhibition of MET, TRK, TIE2 and VEGFR2 kinases (Press release Deciphera Pharmaceuticals, NOV 20, 2014, View Source [SID:1234500992]). Altiratinib exhibited potency against both wild-type and mutant forms of MET and TRK kinases. In in vivo studies, altiratinib was shown to inhibit tumor growth, evasive vascularization, invasion and/or metastasis. In one model an increased overall survival was observed. Altiratinib exhibited anti-tumor activity in a variety of xenograft or allograft tumor models, including melanoma, gastric, lung, colorectal, breast, ovarian and glioblastoma. These data were presented today at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. Altiratinib is currently in a Phase 1 clinical study in cancer patients with solid tumors.

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"In this preclinical data set, the profile observed with altiratinib demonstrated robust and durable inhibition of kinases related to multiple hallmarks of cancer., Our data demonstrate blocking of tumor progression and growth and tumor microenvironment related mechanisms, including evasive vascularization and metastasis in a variety of cancer models," said Michael D. Taylor, PhD, Deciphera’s President and Chief Executive Officer. "We look forward to further evaluation of altiratinib’s anti-cancer activity, including top-line data from our ongoing Phase 1 clinical study in patients with advanced solid tumors which is expected in mid-2015."

In a poster presentation titled "Altiratinib: a balanced inhibitor of MET, TRK, TIE2, and VEGFR2 kinases that exhibits broad anti-tumor and anti-angiogenic activities," Deciphera researchers described data which demonstrated that altiratinib inhibited tumors driven by MET amplification, overexpression, or mutation and also provided the potential for blocking tumor microenvironment angiogenic resistance mechanisms and pro-tumoral effects. Findings from the data include:

Altiratinib potently inhibited MET, TIE2, VEGFR2, and TRK kinases in functional cellular assays, including activity against proliferation, migration, and capillary tube formation, and with sufficient single-digit nanomolar potency such that all of these targets could be effectively inhibited simultaneously in vivo.
Altiratinib exhibited efficacy at preventing tumor growth, as well as inhibiting evasive vascularization, pro-tumoral macrophages, epithelial-to-mesenchymal transition (EMT) and metastasis in a variety of cancer models.
Altiratinib inhibited MET kinase for more than 24 hours after a single 10 mg/kg dose in a gastric cancer xenograft model leading to significant inhibition of tumor growth.
Altiratinib blocked bevacizumab-induced evasive vascularization and EMT in an aggressive, invasive glioblastoma model.
Altiratinib inhibited primary tumor growth and showed additive activity with paclitaxel; in addition, it reduced TIE2-expressing macrophages in the tumor stroma and significantly reduced lung metastases in a metastatic breast cancer model.
Altiratinib exhibited a long off-rate from kinases (greater than 24 hours from TIE2 and TRKA) in a variety of cell-based assays, based on its binding mode.
Altiratinib inhibited microvessel density and tumor growth in a xenograft model where both TIE2 and VEGFR2 kinases contribute to vessel growth.
Altiratinib compared favorably with other multi-targeted MET inhibitors, and had additional activity in inhibiting oncogenic MET mutants found in papillary renal cell carcinoma (PRCC), while other MET inhibitors have not been shown to inhibit activated MET mutants.