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1.
J Med Chem ; 57(11): 4720-44, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24819116

ABSTRACT

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Brain/metabolism , Lactams, Macrocyclic/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Aminopyridines , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Crystallography, X-Ray , Drug Resistance, Neoplasm , Humans , Lactams , Lactams, Macrocyclic/pharmacokinetics , Lactams, Macrocyclic/pharmacology , Mice , Microsomes, Liver/metabolism , Models, Molecular , Mutation , NIH 3T3 Cells , Pyrazoles , Rats , Receptor Protein-Tyrosine Kinases/genetics , Stereoisomerism , Structure-Activity Relationship
2.
J Med Chem ; 57(4): 1170-87, 2014 Feb 27.
Article in English | MEDLINE | ID: mdl-24432909

ABSTRACT

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).


Subject(s)
Drug Resistance, Neoplasm/genetics , Point Mutation , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Receptor Protein-Tyrosine Kinases/genetics , Anaplastic Lymphoma Kinase , Crizotinib , Humans
3.
Mol Cancer Ther ; 11(10): 2274-83, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22752429

ABSTRACT

Clinical trials of selective RAF inhibitors in patients with melanoma tumors harboring activated BRAFV600E have produced very promising results, and a RAF inhibitor has been approved for treatment of advanced melanoma. However, about a third of patients developed resectable skin tumors during the course of trials. This is likely related to observations that RAF inhibitors activate extracellular signal-regulated kinase (ERK) signaling, stimulate proliferation, and induce epithelial hyperplasia in preclinical models. Because these findings raise safety concerns about RAF inhibitor development, we further investigated the underlying mechanisms. We showed that the RAF inhibitor PF-04880594 induces ERK phosphorylation and RAF dimerization in those epithelial tissues that undergo hyperplasia. Hyperplasia and ERK hyperphosphorylation are prevented by treatment with the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD-0325901 at exposures that extrapolate to clinically well-tolerated doses. To facilitate mechanistic and toxicologic studies, we developed a three-dimensional cell culture model of epithelial layering that recapitulated the RAF inhibitor-induced hyperplasia and reversal by MEK inhibitor in vitro. We also showed that PF-04880594 stimulates production of the inflammatory cytokine interleukin 8 in HL-60 cells, suggesting a possible mechanism for the skin flushing observed in dogs. The complete inhibition of hyperplasia by MEK inhibitor in epithelial tissues does not seem to reduce RAF inhibitor efficacy and, in fact, allows doubling of the PF-04880594 dose without toxicity usually associated with such doses. These findings indicated that combination treatment with MEK inhibitors might greatly increase the safety and therapeutic index of RAF inhibitors for the treatment of melanoma and other cancers.


Subject(s)
Benzamides/administration & dosage , Benzamides/pharmacology , Diphenylamine/analogs & derivatives , Epithelium/pathology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Animals , Benzamides/chemistry , Diphenylamine/administration & dosage , Diphenylamine/chemistry , Diphenylamine/pharmacology , Dogs , Dose-Response Relationship, Drug , Epidermis/drug effects , Epidermis/pathology , Epithelium/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , HL-60 Cells , Humans , Hyperplasia , Interleukin-8/metabolism , Mice , Mice, Nude , Mitogen-Activated Protein Kinase Kinases/metabolism , Models, Biological , Phosphorylation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Multimerization/drug effects , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Proto-Oncogene Proteins c-raf/metabolism , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry
4.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 6): o1448, 2010 May 26.
Article in English | MEDLINE | ID: mdl-21579519

ABSTRACT

The reaction of 2,4-dichloro-5-(trifluoro-meth-yl)pyrimidine with 1H-pyrazole gave two structural isomers in a 1:1 ratio that were separable by chromatography. The title compound, C(8)H(4)ClF(3)N(4), was the first product to elute and was characterized in the present study to confirm that substitution by the pyrazolyl group had occurred at position 4. The mol-ecule (with the exception of the F atoms) is essentially planar, with a mean deviation of 0.034 Šfrom the least-squares plane through all non-H and non-F atoms. The bond angles in the pyrimidine ring show a pronounced alternating pattern with three angles, including those at the two N atoms being narrower, and the remaining three wider than 120°.

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