Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (Volitinib) as a Highly Potent and Selective Mesenchymal–Epithelial Transition Factor (c-Met) Inhibitor in Clinical Development for Treatment of Cancer

Jia, Hong; Dai, Guangxiu; Weng, Jianyang; Zhang, Zhulin; Wang, Qing; Zhou, Feng; Jiao, Longxian; Cui, Yumin; Ren, Yongxin; Fan, Shiming; Zhou, Ji; Qing, WU; Gu, Yi; Wang, Jian; Sai, Yang; Su, Weiguo

doi:10.1021/jm500510f

Cited by 115 publications

(86 citation statements)

References 19 publications

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“…Combining osimertinib with an agent active on an alternative signaling pathway such as selumetinib (MEK1/2 inhibitor; AZD6244, ARRY-142886) 10 or savolitinib (MET-TKI; AZD6094, HMPL-504, volitinib) 11 may enhance activity in patients with acquired resistance to EGFR-TKIs, or delay the development of subsequent resistance via these alternate routes. Combining EGFR-TKIs with an immune-mediated therapy, such as durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody, MEDI4736], 12 may enhance antitumor immunity through downregulation of PD-L1, as EGFR activation has been shown to induce PD-L1 expression.…”

Section: Introductionmentioning

confidence: 99%

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

et al. 2020

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Background: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. Patients and methods: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25e75 mg p.o. twice a day; continuous or intermittent), savolitinib (600e800 mg p.o. once a day), or durvalumab (3e10 mg/kg intravenous every 2 weeks). Results: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n ¼ 36), savolitinib (n ¼ 18), or durvalumab (n ¼ 23). Most common adverse events (any grade), occurring in 20% of patients across dose groups, were: selumetinib armddiarrhea (75%), rash (58%), nausea (47%); savolitinib armdnausea (67%), rash (56%), vomiting (50%); durvalumab armdrash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n ¼ 1), 50 mg (n ¼ 1), and 75 mg (n ¼ 4) continuous-dose groups, savolitinib 600 mg (n ¼ 1) and 800 mg dose groups (n ¼ 2), and durvalumab 10 mg/kg (n ¼ 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. Conclusion: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. Clinical trials number: NCT02143466.

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Section: Introductionmentioning

confidence: 99%

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

et al. 2020

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“…AZD6094 (savolitinib, HMPL-504) is a novel, potent, and selective MET inhibitor currently in clinical development in various indications, including PRCC (11,12). In preclinical studies, AZD6094 displayed nanomolar in vitro activity against MET and its downstream signaling targets.…”

Section: Introductionmentioning

confidence: 99%

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

Schuller

Barry

Jones

et al. 2015

Clinical Cancer Research

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Purpose: Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.Experimental Design: Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).Results: AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a doseand time-dependent induction of cleaved PARP, a marker of cell death.Conclusions: Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.

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“…Molecular modeling showed that the mutant c-MET was sufficiently distorted to prohibit the binding of the drug. SAVOLITINIB (volitinib, AZD6094) was synthesized by AstraZeneca as a Type I specific c-MET inhibitor [150] and shown initially to be active against gastric and renal cancers xenograft models [151,152]. The drug was subsequently shown to be active against NSCLC models both in vivo and in vitro where it also targets PI3K and MAPK [153].…”

Section: Hepatocyte Growth Factor Receptor (Hfgr C-met)mentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (Volitinib) as a Highly Potent and Selective Mesenchymal–Epithelial Transition Factor (c-Met) Inhibitor in Clinical Development for Treatment of Cancer

Cited by 115 publications

References 19 publications

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

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