2. Academic Validation
  3. Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling

  • Cancers (Basel). 2021 Feb 23;13(4):927. doi: 10.3390/cancers13040927.
Farid Ahmad Siddiqui 1,  Hanna Parkkola 1,  Vladimir Vukic 1 2,  Christina Oetken-Lindholm 1,  Alok Jaiswal 3,  Alexandros Kiriazis 1,  Karolina Pavic 4,  Tero Aittokallio 3 5 6,  Tiina A Salminen 7,  Daniel Abankwa 1 4
Affiliations

Affiliations

  • 1 Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
  • 2 Faculty of Technology, University of Novi Sad, 21000 Novi Sad, Serbia.
  • 3 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland.
  • 4 Cancer Cell Biology and Drug Discovery Group, Department of Life Sciences and Medicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg.
  • 5 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, N-0310 Oslo, Norway.
  • 6 Centre for Biostatistics and Epidemiology (OCBE), Faculty of Medicine, University of Oslo, N-0372 Oslo, Norway.
  • 7 Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland.
PMID: 33672199 DOI: 10.3390/cancers13040927
Abstract

The ATP-competitive inhibitors of HSP90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between HSP90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator Galectin-3 downstream of the HSP90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high Cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for HSP90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 μM-44 μM in vitro. All of the compounds were K-Ras selective, and potently decreased the HSP90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung Cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved HSP90/Cdc37 interface inhibitors in Cancer and other aging-associated diseases.

Keywords

Cdc37; Hsp90; K-Ras; cancer; drug development; nanoclustering.

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