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Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK).
TLDR
A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3, which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties. Expand
An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.
TLDR
The antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms, and the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers is shown. Expand
Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma
TLDR
A strong correlation was observed between antitumor response and inhibition of N PM-ALK phosphorylation and induction of apoptosis in tumor tissue, illustrating the potential clinical utility of inhibitors of NPM-ALK in treatment of patients with ALK-positive ALCL. Expand
PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models.
TLDR
The results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases. Expand
Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2.
TLDR
It is concluded that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm. Expand
Nonclinical Antiangiogenesis and Antitumor Activities of Axitinib (AG-013736), an Oral, Potent, and Selective Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases 1, 2, 3
TLDR
Although axitinib inhibits platelet-derived growth factor receptors and KIT with nanomolar in vitro potencies, based on pharmacokinetic/pharmacodynamic analysis, axitine acts primarily as a VEGFR tyrosine kinase inhibitor at the current clinical exposure. Expand
Activation of 5′-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase Iϵ (CKIϵ)-dependent Degradation of Clock Protein mPer2*
TLDR
It is concluded that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm. Expand
Sensitivity of Selected Human Tumor Models to PF-04217903, a Novel Selective c-Met Kinase Inhibitor
TLDR
Results show the use of highly selective inhibition of c-Met and provide insight toward targeting tumors exhibiting different mechanisms ofc-Met dysregulation, and also show potent antiangiogenic properties in vitro and in vivo. Expand
Importance of the proline-rich region following signal-anchor sequence in the formation of correct conformation of microsomal cytochrome P-450s.
TLDR
It is proposed that the proline residues in the prolines of cytochrome P450(M1) are crucial for the formation of the correct conformation of microsomal P-450 molecules. Expand
Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective
This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collectiveExpand
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