New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells.
Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases. As a result cancer cells are able to suppress apoptosis and develop resistance to cytostatic drugs. To identify HSP27 inhibitors we follow a novel computational drug repositioning approach. We exploit a similarity between a predicted HSP27 binding site to a viral thymidine kinase to generate lead inhibitors for HSP27. Six of these leads were verified experimentally. They bind HSP27 and down-regulate its chaperone activity. Most importantly, all six compounds inhibit development of drug resistance in cellular assays. One of the leads - chlorpromazine - is an antipsychotic, which has a positive effect on survival time in human breast cancer. In summary, we make two important contributions: First, we put forward six novel leads, which inhibit HSP27 and tackle drug resistance. Second, we demonstrate the power of computational drug repositioning.
Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
Jörg C
JC
Heinrich
Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
Sainitin
S
Donakonda
Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
V Joachim
VJ
Haupt
B CUBE - Center for Molecular Bioengineering, Technische Universität Dresden, 01307 Dresden, Germany.
Petra
P
Lennig
B CUBE - Center for Molecular Bioengineering, Technische Universität Dresden, 01307 Dresden, Germany.
Yixin
Y
Zhang
Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
Michael
M
Schroeder
D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002746:Chlorpromazine / Q000737:chemistry / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods*; D054697:Cytostatic Agents / Q000737:chemistry / Q000494:pharmacology*; D058492:Drug Repositioning / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding
D014150:Antipsychotic Agents; D054697:Cytostatic Agents; D055551:HSP27 Heat-Shock Proteins; D002746:Chlorpromazine
BVDU; HSPB1; binding site; drug repositioning; drug repurposing