SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor growth in vivo by inducing G2/M cell cycle arrest.
Protein kinase D (PKD) has been implicated in many aspects of tumorigenesis and progression, and is an emerging molecular target for the development of anticancer therapy. Despite recent advancement in the development of potent and selective PKD small molecule inhibitors, the availability of in vivo active PKD inhibitors remains sparse. In this study, we describe the discovery of a novel PKD small molecule inhibitor, SD-208, from a targeted kinase inhibitor library screen, and the synthesis of a series of analogs to probe the structure-activity relationship (SAR) vs. PKD1. SD-208 displayed a narrow SAR profile, was an ATP-competitive pan-PKD inhibitor with low nanomolar potency and was cell active. Targeted inhibition of PKD by SD-208 resulted in potent inhibition of cell proliferation, an effect that could be reversed by overexpressed PKD1 or PKD3. SD-208 also blocked prostate cancer cell survival and invasion, and arrested cells in the G2/M phase of the cell cycle. Mechanistically, SD-208-induced G2/M arrest was accompanied by an increase in levels of p21 in DU145 and PC3 cells as well as elevated phosphorylation of Cdc2 and Cdc25C in DU145 cells. Most importantly, SD-208 given orally for 24 days significantly abrogated the growth of PC3 subcutaneous tumor xenografts in nude mice, which was accompanied by reduced proliferation and increased apoptosis and decreased expression of PKD biomarkers including survivin and Bcl-xL. Our study has identified SD-208 as a novel efficacious PKD small molecule inhibitor, demonstrating the therapeutic potential of targeted inhibition of PKD for prostate cancer treatment.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
Manuj
M
Tandon
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
Joseph M
JM
Salamoun
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
Evan J
EJ
Carder
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
Elisa
E
Farber
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
Shuping
S
Xu
Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Fan
F
Deng
Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas, 75708, United States of America.
Hua
H
Tang
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
Peter
P
Wipf
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
Q Jane
QJ
Wang
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011621:Pteridines / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D009363:Neoplasm Proteins; D011621:Pteridines; C511004:SD-208; C089212:protein kinase D; D011493:Protein Kinase C