title: Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions.
abstract: Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.
authors: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , 555 Zuchongzhi Lu, Building 3, Room 426, Pudong, Shanghai 201203, China.
authors: Meining
authors: M
authors: Wang
authors: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , Shanghai 201203, China.
authors: Aijun
authors: A
authors: Shen
authors: Department of Medicinal Chemistry, China Pharmaceutical University , Nanjing 210009, China.
authors: Chi
authors: C
authors: Zhang
authors: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , 555 Zuchongzhi Lu, Building 3, Room 426, Pudong, Shanghai 201203, China.
authors: Zilan
authors: Z
authors: Song
authors: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , Shanghai 201203, China.
authors: Jing
authors: J
authors: Ai
authors: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , Shanghai 201203, China.
authors: Hongchun
authors: H
authors: Liu
authors: Department of Medicinal Chemistry, China Pharmaceutical University , Nanjing 210009, China.
authors: Liping
authors: L
authors: Sun
authors: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , Shanghai 201203, China.
authors: Jian
authors: J
authors: Ding
authors: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , Shanghai 201203, China.
authors: Meiyu
authors: M
authors: Geng
authors: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , 555 Zuchongzhi Lu, Building 3, Room 426, Pudong, Shanghai 201203, China.
authors: Ao
authors: A
authors: Zhang
mesh_terms: D000818:Animals; D004351:Drug Resistance / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D011505:Protein-Tyrosine Kinases