Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100

  • Bioorg Med Chem Lett. 2015 Nov 15;25(22):5254-7. doi: 10.1016/j.bmcl.2015.09.053.
Se-Ho Kim  1 ,  Rajendra Tangallapally  2 ,  In Chul Kim  3 ,  Richard Trovato  4 ,  Daniel Parker  5 ,  J Scott Patton  6 ,  Leslie Reeves  7 ,  Chad Bradford  8 ,  Daniel Wettstein  9 ,  Vijay Baichwal  10 ,  Damon Papac  11 ,  Ashok Bajji  12 ,  Robert Carlson  13 ,  Kraig M Yager  14
Affiliations
  • 1. Orthobond Corporation, 675 U.S. 1, North Brunswick, NJ 08902, USA. Electronic address: [email protected].
  • 2. St Jude Children's Research Hospital, Department of Chemical Biology, 262 Danny Thomas Place, Memphis, TN 38105, USA.
  • 3. New Hope Baptist Church, 149 Highland Ave., East Lansing, MI 48823, USA.
  • 4. Jacobs Engineering, 155 N, 400 W., Suite 550, Salt Lake City, UT 84103, USA.
  • 5. AvidXchange, 6415 South, 3000 East, Suite 150, Salt Lake City, UT 84121, USA.
  • 6. Arup Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108, USA.
  • 7. Genysis Labs, 391 Orange St, Salt Lake City, UT 84104, USA.
  • 8. Sera Prognostics, 2749 East Parleys Way, Suite 200, Salt Lake City, UT 84109, USA.
  • 9. MediProPharma, 419 Wakara Way, #207B, Salt Lake City, UT 84108, USA.
  • 10. Core Diagnostics, 2458 Embarcadero Way, Palo Alto, CA 94303, USA.
  • 11. Navigen, 383 Colorow Dr, Salt Lake City, UT 84108, USA.
  • 12. VioGen Biosciences, 1290 West, 2320 South, Suite E, Salt Lake City, UT 84119, USA.
  • 13. Karyopharm Therapeutics, 85 Wells Ave., 2nd Floor, Newton, MA 02459, USA.
  • 14. Myriad Genetic Laboratories, 320 Wakara Way, Salt Lake City, UT 84108, USA. Electronic address: [email protected].
PMID: 26483201 DOI: 10.1016/j.bmcl.2015.09.053
Abstract

Various types of HSP90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic HSP90 Inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation.

Keywords
Chromatography-free synthesis; Clinical candidate; Hsp90 inhibitors; Prodrugs; Salt screening.
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