James D Winkler

Array BioPharma Inc., Boulder, Colorado, United States

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Publications (6)26.28 Total impact

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    ABSTRACT: Current therapies for treating skeletal pain have significant limitations as available drugs (non-steroidal anti-inflammatory drugs and opiates) have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomysin receptor kinase A (TrkA) has recently become an attractive target for inhibition of adult skeletal pain. Here we explore whether sustained administration of a selective small molecule Trk inhibitor that blocks TrkA, TrkB and TrkC kinase activity with nanomolar affinity reduces skeletal pain while allowing the maintenance of sensory and sympathetic neurons in the adult mouse. Twice-daily administration of a Trk inhibitor was begun 1 day post fracture and within 8 h of acute administration fracture pain-related behaviors were reduced by 50% without significant sedation, weight gain or inhibition of fracture healing. Following administration of the Trk inhibitor for 7 weeks, there was no significant decline in the density of unmyelinated or myelinated sensory nerve fibers, sympathetic nerve fibers, measures of acute thermal pain, acute mechanical pain, or general neuromuscular function. The present results suggest that sustained administration of a peripherally selective TrkA, B and C inhibitor significantly reduces skeletal pain without having any obvious detrimental effects on adult sensory and sympathetic nerve fibers or early fracture healing. As with any potential therapeutic advance, understanding whether the benefits of Trk blockade are associated with any risks or unexpected effects will be required to fully appreciate the patient populations that may benefit from this therapeutic approach.
    Bone 02/2011; 48(2):389-98. · 4.46 Impact Factor
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    ABSTRACT: Finding new therapies to assist in the treatment of cancer is a major challenge of clinical research. Small molecules that inhibit different molecular targets at the different levels of the MAPK pathway have been developed. Several MEK inhibitors have been examined in early-phase clinical trials and the current state of clinical results using these therapies is presented here.
    Biochimica et Biophysica Acta 09/2007; 1773(8):1248-55. · 4.66 Impact Factor
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    ABSTRACT: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models. The ability of ARRY-142886 to inhibit purified MEK1 as well as other kinases was evaluated. Its effects on extracellular signal-regulated kinase (ERK) phosphorylation and proliferation in several cell lines were also determined. Finally, the inhibitor was tested in HT-29 (colorectal) and BxPC3 (pancreatic) xenograft tumor models. The IC(50) of ARRY-142886 was determined to be 14 nmol/L against purified MEK1. This activity is not competitive with ATP, which is consistent with the high specificity of compound for MEK1/2. Basal and epidermal growth factor-induced ERK1/2 phosphorylation was inhibited in several cell lines as well as 12-O-tetradecanoylphorbol-13-acetate-induced ERK1/2 phosphorylation in isolated peripheral blood mononuclear cells. Treatment with ARRY-142886 resulted in the growth inhibition of several cell lines containing B-Raf and Ras mutations but had no effect on a normal fibroblast cell line. When dosed orally, ARRY-142886 was capable of inhibiting both ERK1/2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions were also seen in a BxPC3 xenograft model. In addition, tumors remained responsive to growth inhibition after a 7-day dosing holiday. ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies.
    Clinical Cancer Research 04/2007; 13(5):1576-83. · 7.84 Impact Factor
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    ABSTRACT: The role of MEK 1,2 in cancer tumorgenesis has been clearly demonstrated preclinically, and two selective inhibitors are currently undergoing clinical evaluation to determine their role in the human disease. We have discovered 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones as a new class of ATP noncompetitive MEK inhibitors. These inhibitors exhibit excellent cellular potency and good pharmacokinetic properties and have demonstrated the ability to inhibit ERK phosphorylation in HT-29 tumors from mouse xenograft studies.
    Journal of Medicinal Chemistry 02/2006; 49(2):441-4. · 5.61 Impact Factor
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    ABSTRACT: This paper reviews recent progress in the design and evaluation of MEK inhibitors as cancer therapeutics. Activation of the Ras / Raf / MEK / MAP kinase pathway has been implicated in uncontrolled cell proliferation and tumor growth. Mutated, oncogenic forms of Ras are found in 50% of colon, 90% of pancreatic and 30% of lung cancers. Recently, B-Raf mutations have been identified in more than 60% of malignant melanomas and from 40-70% of papillary thyroid cancers. MEK, a dual specificity kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. Representative examples of both ATP competitive and non-competitive inhibitors as well as natural product based inhibitors will be discussed.
    Current Topics in Medicinal Chemistry 02/2005; 5(2):215-29. · 3.70 Impact Factor
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    ABSTRACT: MEK 1,2 is downstream of both Ras and Raf. Its only known substrates are ERK 1,2, while the only known activators of ERK 1,2 are MEK 1,2. Cell lines and primary tumor samples have demonstrated constitutive activation of the ERK pathway in cancers of the pancreas, kidney, lung, ovary and colon. Additionally, two oncogenic mutations reside in this pathway. Mutated forms of Ras are found in 30% of all human cancers, more specifically, >90% pancreatic, 50% of colon and 30% lung cancers. Recently, B-Raf mutations have also been found in more than 60% of malignant melanoma and in a significant proportion of papillary thyroid cancers (40-70%). A constitutively active ERK kinase cascade is the result of these mutant proteins. With the role of MEK 1,2 in cancer tumorigeneis demonstrated pre-clinically, two selective MEK 1,2 inhibitors are currently undergoing clinical evaluation to determine their role in the human disease. We have discovered a new class of ATP noncompetitive MEK 1,2 inhibitors: 4-(4-bromo-2-fluorophenylamino)-1-methyl-pyridin-2(1H)ones. These inhibitors are highly selective with less than 50% inhibition observed at 10 mM against a panel of over 20 kinases. They are extremely potent inhibitors with cellular IC50's as low as 2 nM in mechanistic assays and 11 nM in functional assays, respectively. This class of MEK 1,2 inhibitors demonstrates excellent developability characteristics with low hepatic clearance, high permeability and excellent bioavailability in rodents (53 to 100% range within the class). Finally, these inhibitors have shown the ability to inhibit ERK phosphorylation in HT-29 tumors in mouse xenograft studies. Our work clearly demonstrates that 4-(4-bromo-2-fluorophenylamino)-1-methyl-pyridin-2(1H)ones are a new class of selective, orally active MEK 1,2 inhibitors with excellent anti-cancer properties.