PF-02341066 – A DUAL c-MET/ALK INHIBITOR

by Selleckchem | Mar 20 2012

Introduction: Either ALk or MET

The inhibition of the transmembrane protein cMET demonstrated some notable success in the treatment of various different metabolic disorders. However, one of the key points which leads potent molecule to fail the phase I and II testing in reference to the mammalian system is the often extreme toxicity observed [1]. A potent inhibitor that failed screening in this fashioned was PHA-665752 [2], but structural studies with this molecule showed a binding conformation in the ATP domain of the tyrosine kinase section of the protein that could be adapted to different molecular structures. Utilizing this information a series of structurally related molecules were derived and screened for activity against cMET. In this way the PF-02341066 c-Met inhibitor was discovered and animal testing demonstrated anti-tumor activity [3;4]. Closer investigations into the new molecule revealed that not only cMET was being inhibited but PF-02341066 also had activity towards ALK [4-6]. ALK is an acronym for anaplastic lymphoma kinase and is classified in the same group as leukocyte tyrosine kinases as part of the insulin super family. Previously ALK had not been considered an essential target during chemotherapeutic action but PF-02341066 demonstrated greater sensitivity than could be accounted for by cMET inhibition alone. Crucially ALK mutations have been discovered in several types of disorders such as Non small cell lung cancer, inflammatory myoflibroblastic tumors and anaplastic large cell lymphomas. PF-02341066 was determined to be active in many of the mutational situations promoting its expanded investigation into clinical trials.

PF-02341066: Properties and Availability

Developed in the Pfizer research laboratories from the skeletal structure of the MET inhibitor PHA-665752, the PF-02341066 structure was designed to be a cMET inhibitor with lower toxicity and greater pharmacokinetic properties. Consisting of a core benzyloxypyridine structure PF-02341066 was demonstrated to have a similar IC50 for cMET compared to PHA-665752 (8&9nM respectively) However, in addition to cMET activity was determined towards ALK with a PF-02341066 IC50 of 20 nM. PF-02341066 solubility in DMSO was limited to 25 mg/ml with slight warming with a similar finding for ethanol, however solubility in water was very poor limiting aqueous solutions to a maximum of 10-20 µM. If stored at -20°C the solid form of PF-02341066 can be kept for upwards of 2 years prior to retesting of purity. PF-02341066 stability in solution is problematic in that decay in stock concentrations is observed after 2-4 hr at room temperature. PF-02341066 suppliers can be located quite easily with PF-02341066 prices ranging from $66 to $320 for 10mg free base for those wishing to buy PF-02341066.

PF-02341066: Preclinical Investigations

PF-02341066 is currently in phase I, II and III clinical trials under the trade name of Crizotinib and the oral formulation name of Xalkori capsules. Preclinical testing of PF-02341066 began with testing in relation to cMET inhibition demonstrating significant activity in cMET mutated cell lines [3]. Upon closer examination ALK activity was determined to be the prime driving force behind the chemotherapeutic action of this molecule [6;7]. EML4-ALK mutation in non small cell lung cell lines were determined to be more sensitivity to PF-02341066 treatment in comparison to standard first line drugs [8;9]. Phase II and III trials in non small cell lung cancer patients demonstrated the efficacy of this moleculer and determined the requirement for ALK status to be screened prior to treatment [10;11].

PF-2341066: Clinical Status

In August of 2011 PF-0231066 was approved for the use in locally advanced or metastatic non small cell lung cancer as first line treatment provide a positive diagnostic indication was given for ALK status. The FDA approval also included the specific analytical technique for determining the Patient ALK status - Vysis ALK Break-Apart FISH Probe Kit manufactured by Abbott Molecular, Inc. In addition to the FDA approval PF-02341066 clinical trials in the safety and pharmacokinetic / dynamics of the oral capsules are ongoing in significantly advance tumors. While PF-02341066 is generally well tolerated 1.6% of patients treated experience extreme toxicity usually to the point of death but this is considered acceptable with 50% of patient’s demonstrated partial responses to treatment over a significant time period.

References

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2. Crosswell HE, Dasgupta A et al. PHA665752, a small-molecule inhibitor of c-Met, inhibits hepatocyte growth factor-stimulated migration and proliferation of c-Met-positive neuroblastoma cells. BMC Cancer 2009; 9:411.

3. Timofeevski SL, McTigue MA et al. Enzymatic characterization of c-Met receptor tyrosine kinase oncogenic mutants and kinetic studies with aminopyridine and triazolopyrazine inhibitors. Biochemistry 2009; 48(23):5339-5349.

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