Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100.
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.
Orthobond Corporation, 675 U.S. 1, North Brunswick, NJ 08902, USA. Electronic address: seho.kimkim@gmail.com.
Se-Ho
SH
Kim
St Jude Children's Research Hospital, Department of Chemical Biology, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Rajendra
R
Tangallapally
New Hope Baptist Church, 149 Highland Ave., East Lansing, MI 48823, USA.
In Chul
IC
Kim
Jacobs Engineering, 155 N, 400 W., Suite 550, Salt Lake City, UT 84103, USA.
Richard
R
Trovato
AvidXchange, 6415 South, 3000 East, Suite 150, Salt Lake City, UT 84121, USA.
Daniel
D
Parker
Arup Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108, USA.
J Scott
JS
Patton
Genysis Labs, 391 Orange St, Salt Lake City, UT 84104, USA.
Leslie
L
Reeves
Sera Prognostics, 2749 East Parleys Way, Suite 200, Salt Lake City, UT 84109, USA.
Chad
C
Bradford
MediProPharma, 419 Wakara Way, #207B, Salt Lake City, UT 84108, USA.
Daniel
D
Wettstein
Core Diagnostics, 2458 Embarcadero Way, Palo Alto, CA 94303, USA.
Vijay
V
Baichwal
Navigen, 383 Colorow Dr, Salt Lake City, UT 84108, USA.
Damon
D
Papac
VioGen Biosciences, 1290 West, 2320 South, Suite E, Salt Lake City, UT 84119, USA.
Ashok
A
Bajji
Karyopharm Therapeutics, 85 Wells Ave., 2nd Floor, Newton, MA 02459, USA.
Robert
R
Carlson
Myriad Genetic Laboratories, 320 Wakara Way, Salt Lake City, UT 84108, USA. Electronic address: kraig.yager@gmail.com.
Kraig M
KM
Yager
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D052117:Benzodioxoles / Q000737:chemistry* / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D000882:Haplorhini; D006801:Humans; D008698:Mesylates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D014867:Water
C577050:1-(4-(2-(6-amino-8-((6-bromo-1,3-benzodioxol-5-yl)sulfanyl)-9H-purin-9-yl)ethyl)piperidin-1-yl)-2-hydroxypropan-1-one; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D008698:Mesylates; D011355:Prodrugs; D014867:Water; C000608570:MPC-0767; D000225:Adenine; D000409:Alanine
Chromatography-free synthesis; Clinical candidate; Hsp90 inhibitors; Prodrugs; Salt screening