Cancer Metabolism Inhibitors
Cancer Metabolism Inhibitor Program
MPC-8640 is the lead preclinical compound in our Cancer Metabolism Inhibitor (CMI) program and is being developed by Myrexis as a drug candidate for the treatment of a variety of cancers. It is currently in investigational new drug (IND) enabling studies.
Page Contents
- About the CMI program
- CMI companion diagnostic
- About Nicotinamide Phosphoribosyltransferase (NAMPT)
- Recent Presentations on CMI program
- References
About the CMI program
MPC-8640 is an orally bioavailable pro-drug of a follow-on molecule to our prior CMI drug candidate, MPC-9528, that has enhanced solubility and distinct pharmacokinetic advantages and is being developed for the treatment of cancer. Both the active moiety of MPC-8640 as well as MPC-9528 inhibit Nicotinamide phosphoribosyltransferase (Nampt) in vitro and in cells at picomolar drug concentrations and are tumoricidal in every cancer line tested to date representing 17 different tumor tissue types [1][2][3][4][12]. Both compounds display on-target activity in tumor cells by potently reducing NAD levels, which leads to inhibition of glycolysis, energy deprivation and cell death, while NAD in normal tissues is less affected. In animal models, MPC-9528 administered on a variety of dosing schedules causes dramatic tumor regressions across multiple tumor types and is well tolerated [6][11][12]. This anti-tumor activity is dose-dependent and tightly correlated to the level of NAD depletion, confirming the on-target mechanism of action for MPC-9528 activity [8]. The sensitivity of tumor cells to MPC-9528 in vitro appears to parallel its anti-tumor potency in xenograft models and was linked to basal Nampt expression levels. Nampt expression levels may therefore have utility for predicting tumor response to Nampt inhibitors [8].
MPC-9528 has been shown to exhibit synergistic anti-tumor activity when coupled with DNA alkylating agents, such as temozolomide, and thymidylate synthase inhibitors, such as Fluorouracil (5-FU) [5][9]. These common classes of chemotherapy drugs also reduce cellular NAD levels as a result of their mechanism of action, specifically by activating the NAD-consuming enzyme poly(ADP-ribose) polymerase (PARP) [9]. The mechanism of action of MPC-9528 is distinct from these other agents, leading to a combined effect on reducing cellular NAD levels and synergistic anti-tumor activity [5][9]. These data support the potential of Nampt inhibitors for broad spectrum tumoricidal activity as monotherapy and in a variety of combinations with other agents.
Additional preclinical studies on MPC-9528 and MPI-0487316, a structurally distinct Nampt inhibitor, demonstrate that oral administration of either MPC-9528 or MPI-0487316 resulted in tumor regressions in animal model studies across multiple dosing schedules [11]. MPC-8640 is a pro-drug of MPI-0487316 with enhanced solubility and distinct pharmacokinetic advantages [12]. MPC-8640 is primed to be the best-in-class Nampt inhibitor with potential for treating a wide variety of cancers. We are currently conducting IND enabling studies on MPC-8640.
CMI Companion Diagnostic
In normal healthy cells, the NAD-reducing and tumoricidal activity of MPC-9528 can be completely blocked by nicotinic acid (niacin, Vitamin B3) [3][7]. Nicotinic acid is converted to NAD through an alternative pathway that is dependent upon the enzyme Nicotinic Acid Phosphoribosyltransferase (Naprt1) and does not utilize Nampt [3][10]. Experiments at Myrexis have found that approximately 40% of tumor cell lines are deficient in Naprt1, and in these cells, nicotinic acid had little to no effect on MPC-9528 tumoricidal activity [10]. Furthermore, we found that combining nicotinic acid with MPC-9528 increases the tolerated MPC-9528 dose while still causing in vivo killing of xenograft tumors deficient in Naprt1. This demonstrates the potential to combine nicotinic acid and MPC-9528 to treat patients with tumors that are deficient in Naprt1. A diagnostic method designed to measure Naprt1 expression could be used to identify those patients with Naprt1 deficient tumors that are most likely to respond to the combination therapy.
About Nicotinamide Phosphoribosyltransferase (Nampt)
Nampt catalyzes the first step in the recycling of nicotinamide into NAD and was validated as a new anti-cancer target through the company's chemical proteomics platform. Cancer cells develop dependence on NAD due to increased energy requirements and the elevated activity of NAD consuming enzymes such as mono and poly(ADP-ribose) polymerases (PARPs). Nampt has been shown to be up-regulated in colon and brain cancer and its activity is critical to several pathways relevant to cancer including glucose metabolism, DNA repair and gene expression.
Recent Presentations on CMI program
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Pharmacokinetics, anti-tumor activity and therapeutic index of Nampt inhibitor MPC-8640 in mice |
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Activity of the cancer metabolism inhibitor MPC-9528 in xenograft models: Comparison of different dosing schedules. |
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Coadministration of nicotinic acid with the Nampt inhibitor MPC-9528 enhances anti-tumor activity in Naprt deficient cancer cells in culture and in xenografts |
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The Nampt inhibitor MPC-9528 synergizes with DNA damaging agents |
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Basal NAD levels and Nampt expression correlate with in vitro and in vivo sensitivity of tumor cell lines to the Nampt inhibitor MPC-9528 |
References
1. Fleischer T.C. et al. MPI-0486348: A novel inhibitor of nicotinamide phosphoribosyltransferase induces tumor regreassion in a preclinical model. 101st Annual Meeting of the American Association for Cancer Research (AACR), 2010 in Wahington, DC. Poster PDF 
2. Fleischer T.C. et al. Identifying the target of an orphan compound: CB30865 is a Nampt inhibitor. 101st Annual Meeting of the American Association for Cancer Research (AACR), 2010 in Wahington, DC. Poster PDF
3. Boniface J.J. et al. MPC-9528, a cancer metabolism inhibitor, demonstrates greater therapeutic index in a Naprt1 deficient cancer xenograft model with co-administration of nicotinic acid. Cancer and Metabolism: Pathways to the Future Symposium, September 19-21, 2010, Edinburgh, Scotland. Poster PDF
4. Fleischer T.C. et al. Anti-Tumor Activity of MPC-9528, GMX1778, and APO866: Nampt Inhibitors of Three Structural Classes. November 16-19, 2010, AACR-NCI-EORTC Molecular Targets and Cancer Therapeutic, Berlin, Germany. Poster PDF
5. Terry-Lorenzo R.T. et al. The Nampt inhibitor MPC-9528 and the PARP inhibitor olaparib synergize in killing a BRCA--deficient cancer cell line. November 16-19, 2010, AACR-NCI-EORTC Molecular Targets and Cancer Therapeutic. Berlin, Germany. Poster PDF
6. Baichwal V.R. et al. The cancer metabolism inhibitor MPC-9528 induces tumor regression in xenograft models with multiple dosing schedules by causing rapid and sustained reduction in tumor NAD. 102nd Annual Meeting of the American Association for Cancer Research (AACR), 2011 Orlando, FA. Poster PDF
7. Mather G.G. et al. Administration of Nicotinic Acid Reduces or Prevents Adverse Effects of MPC-9528, A Potent and Selective Nampt Inhibitor. 102nd Annual Meeting of the American Association for Cancer Research (AACR), 2011 Orlando, FA. Poster PDF
8. Boniface J.J. et al. Basal NAD levels and Nampt expression correlate with in vitro and in vivo sensitivity of tumor cell lines to the Nampt inhibitor MPC-9528. 102nd Annual Meeting of the American Association for Cancer Research (AACR), 2011 Orlando, FA. Poster PDF
9. Terry-Lorenzo R.T. et al. The Nampt inhibitor MPC-9528 synergizes with DNA damaging agents. 102nd Annual Meeting of the American Association for Cancer Research (AACR), 2011 Orlando, FA. Poster PDF
10. Fleischer T.C. et al. Coadministration of nicotinic acid with the Nampt inhibitor MPC-9528 enhances anti-tumor activity in Naprt deficient cancer cells in culture and in xenografts. 102nd Annual Meeting of the American Association for Cancer Research (AACR), 2011 Orlando, FA. Poster PDF
11. Baichwal V.R. et al. Activity of the cancer metabolism inhibitor MPC-9528 in xenograft models: Comparison of different dosing schedules. Annual Meeting of the American Society of Clinical Oncology (ASCO), 2011 Chicago, IL. Poster PDF
12. Carlson, R.O. et al. Pharmacokinetics, anti-tumor activity and therapeutic index of Nampt inhibitor MPC-8640 in mice. AACR-NCI-EORTC November 12-16, 2011 San Francisco, CA. Poster PDF
