BIIB021, an Hsp90 inhibitor: A promising therapeutic strategy for blood malignancies (Review).

Abstract

Heat shock proteins (HSPs) are molecular chaperones that are consistently increased to help cells survive under conditions of stress. As a member of the Hsps, Hsp90 is involved in protein post‑translational maturation and disposition. This protein is ubiquitously expressed in normal cells. However, in cancer cells and particularly in hematological malignancies, Hsp90 is unexpectedly abundant to maintain levels of proteins vital for cancer pathology. Hsp90 inhibitors can target the ATP domain of Hsp90 and prohibit its exchange of ADP for ATP, leading to the degradation of client proteins and disruption of signaling cascades. Concomitantly, Hsp90 inhibitors induce tumor cell apoptosis, promote cell cycle arrest and abrogate microenvironment‑derived cytoprotection. Geldanamycin, a benzoquinone antineoplastic antibiotic isolated from the bacterium Streptomyces hygroscopicus, and its derivative, 17‑AAG, were first developed as Hsp90 inhibitors and exhibited effective anticancer potency. Whereas, severe side effects and low solubility restricted their application at the clinical level, BIIB021, a novel and fully synthetic inhibitor of Hsp90, is water soluble and well‑tolerated. Beyond degrading oncogenic protein, BIIB021 can overcome multidrug resistance and potentiate the effects of other therapeutics. phase I/II trials have been conducted to evaluate the dosing schedules and activity of this agent. The present review focuses on the antitumor profile of BIIB021. Furthermore, given the promising efficacy of BIIB021 in leukemia and lymphoma, this review also discusses current research concerning the treatment of hematologic malignancies by targeting Hsp90.

• Authors: Wei He, Huixian Hu
• Journal: Oncology reports (Oncol Rep) Vol. 40 Issue 1 Pg. 3-15 (Jul 2018) ISSN: 1791-2431 [Electronic] Greece
• PMID: 29749536 (Publication Type: Journal Article, Review)

Chemical References

• 6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine
• HSP90 Heat-Shock Proteins
• Pyridines
• Adenine

Topics

• Adenine (analogs & derivatives, therapeutic use)
• Apoptosis
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics)
• Hematologic Neoplasms (drug therapy, genetics, pathology)
• Humans
• Molecular Targeted Therapy
• Protein Processing, Post-Translational (genetics)
• Pyridines (therapeutic use)