Pre-clinical Programs
Myrexis maintains a fully-integrated and self-sufficient preclinical drug discovery operation designed to identify small molecule modulators of novel targets for development as first first-in-class and/or best-in-class cancer treatments.
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Cancer Program
MPC-9528 (formerly MPI-0486348) is Myrexis’ orally-bioavailable, potent, and selective small molecule inhibitor of the cancer cell metabolism enzyme Nicotinamide phosphoribosyltransferase (Nampt) for the treatment of cancer. Nampt catalyzes the first step in the recycling of nicotinamide into NAD and was validated as an exciting anti-cancer target through Myrexis’ chemical proteomics platform. Cancer cells develop dependence on Nampt due to increased energy requirements and the elevated activity of NAD consuming enzymes. MPC-9528 inhibits Nampt in vitro and in cells at picomolar drug levels and has demonstrated cytotoxicity in every cancer line tested representing 15 different tumor tissue types. In animals, MPC-9528 is highly orally bioavailable, displays on target activity by reducing NAD levels in tumors and causes significant tumor regressions. Myrexis’ Nampt inhibitor, MPC-9528, represents a best-in-class, novel clinical development candidate.
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MPI-0486348: A novel inhibitor of nicotinamide phosphoribosyltransferase induces tumor regression in a preclinical model |
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Identifying the target of an orphan compound: CB30865 is a Nampt inhibitor |
MPI-479605 is a highly potent, selective and potential first-in-class inhibitor of the novel mitotic kinase TTK discovered by Myrexis for the treatment of cancer. TTK (also called Mps1) is essential for mitosis through regulation of proper chromosome attachment to the mitotic spindle and activation of the spindle assembly checkpoint. Reduction of TTK protein levels using RNAi impairs this mitotic checkpoint and results in chromosome missegregation and cell death. TTK inhibition is predicted to have antitumor activity in the absence of the the neuropathy that is dose-limiting for tubulin targeting agents. MPI-479605 is cytotoxic for a wide variety of cancer cell lines in vitro, has favorable pharmacokinetic properties and has exhibited anti-tumor activity in mouse colon carcinoma xenograft models.
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Inhibition of TTK Activates the p53 Pathway |
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Inhibition of TTK Promotes Chromosome Segregation Defects in a Manner Distinct from Inhibitors of Aurora or PLK Mitotic Kinases |
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A Novel Small Molecule Inhibitor of the Mitotic Kinase TTK with Anti- Tumor Activity in Pre-Clinical Models |
MPI-443803 is an orally available, brain penetrant, microtubule destabilizing agent being developed by Myrexis for the treatment of cancer. MPI-443803 was developed in an extensive medicinal chemistry effort to produce an orally bioavailable analogue of Azixa. MPI-443803 is not a prodrug of Azixa, but retains its mechanism of action as a potent inducer of apoptosis that prevents the polymerization of tubulin into microtubules. In preclinical studies, MPI-443803 has shown pro-apoptotic activity in multiple cancer types including pancreatic, breast, colorectal, non-small cell lung, melanoma, ovarian and leukemia. MPI-443803 has demonstrated excellent oral bioavailability, crosses the blood brain barrier and distributes rapidly into the CNS. MPI-443803 may be a promising candidate for development as an oral alternative to Azixa.
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April 22, 2009 AACR 2009; Denver, CO 380KB |
Other Product Candidates
MPI-0485520 is a highly potent, orally bioavailable small molecule inhibitor of I-κ-Kinase-ε (IKKε) a novel drug target for cancer, obesity and diabetes. This potential first-in-class drug candidate is highly selective for IKKε and the closely related Tank Binding Kinase 1 (TBK1) kinase. A significant fraction of breast, colon, and prostate tumor cell lines express both IKKε and TBK1 kinase. These kinases activate the NFkB and IRF3 transcription factor pathways, leading to cancer cell growth via upregulation of proinflammatory cytokines as well as proteins involved in antiapoptosis, cell cycle progression, and angiogenesis. Overexpression of IKKε leads to transformation of normal breast epithelial cells, while reduction of IKKε protein causes growth arrest of breast cancer cell lines and down regulation of important cancer signaling pathways. A small molecule drug that inhibits IKKε/TBK1 is expected to benefit cancer patients with tumors harboring activated IKKε and/or TBK1.
In addition, a recent publication in the journal Cell identified IKKε as a central regulator of chronic inflammation, obesity and diabetes [1][2]. These studies demonstrated that a high-fat diet can increase NFκB activation in mice, which leads to sustained elevation in the level of IKKε in liver, adipocytes, and adipose tissue macrophages. Further, mice in which the gene encoding IKKε was knocked out were found to be protected from high-fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis, and whole-body insulin resistance. These data suggest that inhibitors of IKKε have potential for the treatment of obesity, diabetes and associated diseases.
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April 25-28, 2010 FASEB 2010 Annual Meeting Anaheim, CA 365 KB |
MPI-461359
MPI-461359 is a potent, orally available maturation inhibitor being developed by Myrexis for the treatment of HIV-1 infection. MPI-461359 was discovered in a medicinal chemistry program as a highly potent, broadly acting, small molecule inhibitor of HIV-1 maturation. Pharmacokinetic studies in rodents demonstrate that MPI-46139 is highly orally bioavailable. Based upon its efficacy profile, novel mechanism of action and pharmacokinetic properties, we believe MPI-461359 has potential as a promising new HIV therapeutic.
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ACS Conference March 2010 San Francisco, CA 422 KB |
References
[1] Chiang S.H., et al, The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 2009 138 : 961-975. PMID: 19737522: View Abstract
[2] Olefsky JM. IKKepsilon: a bridge between obesity and inflammation. Cell 2009 138 : 834-836. PMID:19737512: View Abstract
