TY - JOUR
T1 - TRAP1
T2 - a viable therapeutic target for future cancer treatments?
AU - Lettini, Giacomo
AU - Maddalena, Francesca
AU - Sisinni, Lorenza
AU - Condelli, Valentina
AU - Matassa, Danilo Swann
AU - Costi, Maria Paola
AU - Simoni, Daniele
AU - Esposito, Franca
AU - Landriscina, Matteo
PY - 2017/8
Y1 - 2017/8
N2 - INTRODUCTION: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors. Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria. Expert opinion: TRAP1 targeting may represent a promising strategy for cancer therapy, based on the increasing and compelling evidence supporting TRAP1 involvement in human carcinogenesis. However, considering the complexity of TRAP1 biology, future strategies of drug discovery need to improve selectivity and specificity toward TRAP1 respect to other HSP90 paralogs. The characterization of specific human malignancies suitable for TRAP1 targeting is also mandatory.
AB - INTRODUCTION: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors. Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria. Expert opinion: TRAP1 targeting may represent a promising strategy for cancer therapy, based on the increasing and compelling evidence supporting TRAP1 involvement in human carcinogenesis. However, considering the complexity of TRAP1 biology, future strategies of drug discovery need to improve selectivity and specificity toward TRAP1 respect to other HSP90 paralogs. The characterization of specific human malignancies suitable for TRAP1 targeting is also mandatory.
KW - Animals
KW - Antineoplastic Agents
KW - Disease Progression
KW - Drug Design
KW - Drug Discovery
KW - HSP90 Heat-Shock Proteins
KW - Humans
KW - Mitochondria
KW - Molecular Targeted Therapy
KW - Neoplasms
KW - Journal Article
KW - Review
U2 - 10.1080/14728222.2017.1349755
DO - 10.1080/14728222.2017.1349755
M3 - Review article
C2 - 28664757
VL - 21
SP - 805
EP - 815
JO - Expert Opinion on Therapeutic Targets
JF - Expert Opinion on Therapeutic Targets
SN - 1472-8222
IS - 8
ER -