Myrexis MYRX Stock Research - MPC-3100 HSP90 Inhibitor Page
Learn more about heat shock protein 90 (HSP90) inhibitors at HSP90 Central
MPC-3100 HSP90 Inhibitor
- Orally-bioavailable Heat Shock Protein 90 (HSP90) inhibitor: fully synthetic, not related to geldanamycin but binds to same site on HSP90 enzyme, IND filed 4/2009. Structure disclosed in 2011 (see below)- distinct from compounds with ocular toxicity (see further discussion on SNTA research page).
- Broad and significant preclinical activity in mouse tumor models w/o hepatic or renal toxicity seen in geldanamycin analogues (these natural product inhibitors have off-target effects and poor bioavailability).
- Animal studies ongoing to help pick p2 indication and combos. MP487109 backup compound.
- 6/6/11 webcast: Work by MYRX and others is showing that HSP90 inhibitors' benefit appears to be in preventing resistance to targeted inhibitors (such as ALK in lung, bRAF in melanoma)
- 6/6/11 webcast: oral HSP90 inhibitor advantage- combo w/ other oral cancer drugs. also can dose daily to maintain constant blood concentration- appears to be most effective.
- 4/5/11 webcast: The only other oral HSP90 inhibitor [not sure which they are referring to because there have been multiple oral HSP90 inhibitors in development recently, though a couple have been terminated recently] also requires capitsol and cannot be pro-drugged (see discussion below)
- 5/10/11 webcast:
- 5/10/11 webcast: "
- AACR 4/2011 was the first publication of structure, which is unique from other two classes of HSP90 inhibitors - click here to download poster - and see right image below for prodrug and MPC3100 structure. Also demonstrated synergy with targeted cancer therapies erlotinib (Tarceva) and sorafenib (Nexavar)
- AACR 4/2011 and 4/5/11 webcast: first disclosed evaluation of soluble L-alanine ester prodrug MPC-0767 that has improved oral bioavailability vs MPC-3100 which requires a Captisol formulation (licensed from Cydex, now owned by Ligand $LGND), resulting in a potentially greatly reduced daily pill burden for pts (1 vs 8 daily) and lower COGS. PK is similar to MPC-3100, which is the only metabolite detected.
- 4/5/11, 5/10/11, 6/6/11 webcasts:
- Phase 1 in solid and hematological cancers started 2q2009 (NCT00920205, was 21/28 daily tablets and later changed to continuous daily dosing on 28 day cycle (ie, no drug holiday) after sufficient tox studies, up to 40 pts).11/2009 at AACR-NCI-EORTC: PK data confirms oral bioavailability- and drug absorption continues to increase with dose level and is equivalent to doses that were effective in preclinical models, Th=12 hrs- supports continuous once or twice daily dosing.
- Completion of trial has slipped due to needing more cohorts than anticipated. 12/2010, 2/2011, 4/2011, 5/2011: enrolling 7th cohort, no MTD yet. 6/6/11 webcast slide: p1 "nearing completion", next steps to "open IND for pro-drug, initiate phase 2" but no guidance for data release.
- 2/9/11 webcast: may enroll 8th cohort, will complete 1h2011. Surrogates of activity such as HSP70 levels may give an indication that it is ok to stop without further escalating. Also looking at bloodstream concentration in pts, starting with 4th cohort they were at levels that corresponded to anticancer activity in vivo
- 4/5/11 webcast: no hepatic or renal toxicity (no mention of ocular tox yes or no) grade 1 diarrhea and nausea- handle with immodium...expect to finish p1 by middle of 2011 then move on to p2
- 5/10/11 cc: no grade 3-4 drug related toxicity, in 7th cohort, "in final stages of phase 1 trial"...
- 4/5/11 webcast: Plan to
- 5/2011 CC: complete trial 2q2011 and start phase 2 ASAP after that.
- Here is the link to the MYRX patent application related to compounds that inhibit HSP90. (#20100292255 filed May 14, 2010)
- You can't tell the actual lead compound from this filing, but the left image below is the general backbone structure of the class