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Targeting Semaphorin 3C in Prostate Cancer With Small Molecules.
Lee, Chung C W; Munuganti, Ravi Shashi Nayana; Peacock, James W; Dalal, Kush; Jiao, Ivy Z F; Shepherd, Ashley; Liu, Liangliang; Tam, Kevin J; Sedgwick, Colin G; Bhasin, Satyam; Lee, Kevin C K; Gooding, Luke; Vanderkruk, Benjamin; Tombe, Tabitha; Gong, Yifan; Gleave, Martin E; Cherkasov, Artem; Ong, Christopher J.
Affiliation
  • Lee CCW; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Munuganti RSN; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Peacock JW; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Dalal K; Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Jiao IZF; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Shepherd A; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Liu L; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Tam KJ; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Sedgwick CG; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Bhasin S; Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Lee KCK; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Gooding L; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Vanderkruk B; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Tombe T; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Gong Y; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Gleave ME; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Cherkasov A; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Ong CJ; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
J Endocr Soc ; 2(12): 1381-1394, 2018 Dec 01.
Article in En | MEDLINE | ID: mdl-30534631
ABSTRACT
Despite the amenability of early-stage prostate cancer to surgery and radiation therapy, locally advanced and metastatic prostate cancer is clinically problematic. Chemical castration is often used as a first-line therapy for advanced disease, but progression to the castration-resistant prostate cancer phase occurs with dependable frequency, largely through mutations to the androgen receptor (AR), aberrant AR signaling, and AR-independent mechanisms, among other causes. Semaphorin 3C (SEMA3C) is a secreted signaling protein that is essential for cardiac and neuronal development and has been shown to be regulated by the AR, to drive epithelial-to-mesenchymal transition and stem features in prostate cells, to activate receptor tyrosine kinases, and to promote cancer progression. Given that SEMA3C is linked to several key aspects of prostate cancer progression, we set out to explore SEMA3C inhibition by small molecules as a prospective cancer therapy. A homology-based SEMA3C protein structure was created, and its interaction with the neuropilin (NRP)-1 receptor was modeled to guide the development of the corresponding disrupting compounds. Experimental screening of 146 in silico‒identified molecules from the National Cancer Institute library led to the discovery of four promising candidates that effectively bind to SEMA3C, inhibit its association with NRP1, and attenuate prostate cancer growth. These findings provide proof of concept for the feasibility of inhibiting SEMA3C with small molecules as a therapeutic approach for prostate cancer.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies Language: En Journal: J Endocr Soc Year: 2018 Type: Article Affiliation country: Canada

Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies Language: En Journal: J Endocr Soc Year: 2018 Type: Article Affiliation country: Canada