Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer.
A promising agent for use in prostate cancer therapy is the Hedgehog (Hh) signaling pathway inhibitor, cyclopamine. This compound, however, has the potential for causing serious side effects in non-tumor tissues. To minimize these bystander toxicities, we have designed and synthesized two novel peptide-cyclopamine conjugates as prostate-specific antigen (PSA)-activated prodrugs for use against prostate cancer. These prodrugs were composed of cyclopamine coupled to one of two peptides (either HSSKLQ or SSKYQ) that can be selectively cleaved by PSA, converting the mature prodrug into an active Hedgehog inhibitor within the malignant cells. Of the two prodrugs, Mu-SSKYQ-Cyclopamine was rapidly hydrolyzed, with a half-life of 3.2h, upon incubation with the PSA enzyme. Thus, modulating cyclopamine at the secondary amine with PSA-cleavable peptides is a promising strategy for developing prodrugs to target prostate cancer.
Kumar
Srinivas K
SK
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
Roy
Indrajit
I
Anchoori
Ravi K
RK
Fazli
Sarah
S
Maitra
Anirban
A
Beachy
Philip A
PA
Khan
Saeed R
SR
D000595:Amino Acid Sequence; D000818:Animals; D016503:Drug Delivery Systems; D015195:Drug Design; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014704:Veratrum Alkaloids / Q000494:pharmacology*
D053823:Hedgehog Proteins; D009842:Oligopeptides; D011355:Prodrugs; D014704:Veratrum Alkaloids; D017430:Prostate-Specific Antigen; C000541:cyclopamine