MPC-3100 - Hsp90
MPC-3100 – An oral Hsp90 inhibitor
MPC-3100 is a novel, potent, fully-synthetic, orally-bioavailable small molecule inhibitor of Hsp90 designed by Myrexis as a drug candidate for the treatment of cancer.
Page Contents
- About MPC-3100
- Clinical Trials
- About Heat Shock Protein 90
- About MPI-487109 follow on
- Recent Presentations
- References
About MPC-3100
MPC-3100 is a potent, fully synthetic, orally-bioavailable, non-geldanamycin inhibitor of Heat shock protein 90 (Hsp90). Hsp90 is a chaperone protein that plays an important role in regulating the activity and function of numerous signaling proteins, or client proteins, that trigger proliferation of cancer cells. Early Hsp90 inhibitors have been analogs of the natural product molecule geldanamycin. While these drug candidates have demonstrated promising preclinical and clinical proof of concept activity in patients with solid tumors and blood cancers, they have been challenging to develop because of drug related toxicities, including hepatotoxicity, nephrotoxicity and pancreatitis. These toxicities are thought to be “off-target” effects as they do not appear to be related to inhibition of Hsp90. Additional limitations to geldanamycin derivatives include poor solubility, metabolic stability and difficulty in administration.
MPC 3100 inhibits Hsp90 by binding to the same site as geldanamycin analogs and has displayed potent anticancer activity in several in vitro and in vivo models [1] [3]. MPC-3100 has not demonstrated the same hepatic or renal toxicity in vivo as the geldanamycin analogs in nonclinical toxicology studies. MPC-3100 significantly and dose-dependently reduced tumor growth in multiple xenograft studies conducted using a variety of human cancer cell lines. In addition, MPC-3100 was well tolerated. We believe this excellent therapeutic index along with the good oral bioavailability will provide an opportunity for daily oral dosing with MPC-3100.
In 2009, we initiated enrollment of a Phase 1 clinical trial to investigate the safety, tolerability and pharmacokinetics of MPC-3100. In this ongoing study, patients are also being evaluated for a therapeutic response.
Clinical Trials
In 2009, we initiated enrollment of a Phase 1 clinical trial to investigate the safety, tolerability and pharmacokinetics of MPC-3100. Patients are also being evaluated for a therapeutic response. Preliminary data from this trial has demonstrated that MPC-3100 is orally-bioavailable with a half life of approximately 12 hours [2]. Drug absorption has not been maximized and continues to increase with increasing dose. This clinical study has achieved drug levels in patients which exceed the efficacious levels obtained in non-clinical studies without evident safety issues. Moreover, these concentrations of MPC-3100 were achieved in patients in the absence of dose-limiting toxicities. We have also shown significant induction Hsp70 expression, a biomarker and biochemical indicator of MPC-3100 activity, in patients [2].
Click here for more information on Clinical Studies with MPC-3100.
About Heat Shock Protein 90
Heat shock protein 90, or Hsp90, is a chaperone protein that plays an important role in regulating the activity and function of numerous signaling proteins, or client proteins, that trigger proliferation of cancer cells. Important client proteins in cancer include steroid hormone receptors (e.g., glucocorticoid, estrogen), oncogenic protein kinases (e.g., Her-2, Met, Kit), mutated oncogenic proteins (e.g., p53, BCR-Abl) and telomerase h-TERT. Hsp90 is part of a chaperone complex which functions to bind and stabilize these proteins. Inhibition of Hsp90 leads to degradation of the client proteins resulting in growth arrest of cancer cells and subsequent induction of apoptosis.
About MPI-487109 follow on
MPI-487109 is a novel, potent fully-synthetic, orally-bioavailable, small molecule inhibitor of Hsp90. MPI-487109 is being developed by Myrexis, Inc. as a follow-on drug candidate to MPC-3100.
Recent Presentations on MPC-3100
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Anti-tumor Activity of MPC-3100, a Synthetic, Orally Bioavailable Hsp90 Inhibitor, in Animal Models AACR 101st Annual Meeting April 17-21, 2010 Washington, D.C. 594 KB |
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Pharmacokinetic and pharmacodynamic data for MPC-3100, a fully synthetic, orally bioavailable HSP90 inhibitor, in cancer patients AACR-NCI-EORTC Nov 15-19, 2009 Boston, MA 164 KB |
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MPC-3100: A non-natural product Hsp90 inhibitor with anti-tumor activity in preclinical models 20th EORTC-NCI-AACR October 21-24, 2008 Geneva Palexpo Geneva, Switzerland 2.08 MB |
References
- MPC-3100: A non-natural product Hsp90 inhibitor with anti-tumor activity in preclinical models. 20th EORTC-NCI-AACR, October 21-24, 2008 in Geneza, Switzerland. Poster PDF
- Pharmacokinetic and pharmacodynamic data for MPC-3100, a fully synthetic, orally bioavailable HSP90 inhibitor, in cancer patients. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, November 18th, 2009 in Boston, MA. Poster PDF
- Anti-tumor Activity of MPC-3100, a Synthetic, Orally Bioavailable Hsp90 Inhibitor, in Animal Models. AACR 101st Annual Meeting of the American Association for Cancer Research (AACR), 2010 in Washington, D.C. Poster PDF
