Development of two novel benzoylphenylurea sulfur analogues and evidence that the microtubule-associated protein tau is predictive of their activity in pancreatic cancer.
In this work, we evaluated two lead compounds, referred to as SG410 and SG430, obtained from a screen of sulfur benzoylphenylurea analogues, against in vitro and in vivo models of pancreas cancer. Both drugs showed a similar mechanism of action profile, with SG410 being more potent as an inhibitor of tubulin assembly. We determined the best in vivo administration schedule and tested SG410 and SG430 in nine cases of a novel platform of direct pancreas cancer xenografts. Both compounds had antiproliferative activity in vitro in the low nanomolar range, but only SG410 showed significant activity in vivo. Administration of SG410 resulted in significant tumor growth delay in five of nine groups tested. In a direct comparison in three of the cases, SG410 was at least as efficacious as docetaxel. We also sought markers that would be predictive of the efficacy of these agents, and we found such a marker in microtubule-associated protein tau (MAPT). This protein enhances the assembly and stability of microtubules. In both the cell lines and the direct human xenografts, MAPT mRNA and protein levels correlated well. There was also a statistically significant inverse correlation between MAPT expression and sensitivity to the tested agents. In summary, the novel sulfur benzoylphenylurea SG410 showed activity inversely related to MAPT expression in a preclinical model of pancreatic cancer comparable with that observed with docetaxel, another microtubule-targeting agent.
Jimeno
Antonio
A
Gastrointestinal Cancer Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21231-1000, USA.
Hallur
Gurulingappa
G
Chan
Audrey
A
Zhang
Xiangfeng
X
Cusatis
George
G
Chan
Fonda
F
Shah
Preeti
P
Chen
Rongbing
R
Hamel
Ernest
E
Garrett-Mayer
Elizabeth
E
Khan
Saeed
S
Hidalgo
Manuel
M
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000737:chemistry*; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013455:Sulfur / Q000737:chemistry*; D043823:Taxoids / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D043823:Taxoids; D014404:Tubulin; D016875:tau Proteins; D000077143:Docetaxel; D013455:Sulfur