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Is the fate of clinical candidate Arry-520 already sealed? Predicting resistance in Eg5-inhibitor complexes

DOI: 10.1158/1535-7163.MCT-19-0154 DOI Help

Authors: Rose-Laure Indorato (Université Grenoble Alpes, CNRS) , Sandeep K. Talapatra (UCL School of Pharmacy) , Fangzhu Lin (UCL School of Pharmacy) , Shozeb Haider (UCL School of Pharmacy) , Simon P. Mackay (University of Strathclyde) , Frank Kozielski (UCL School of Pharmacy) , Dimitrios A. Skoufias (Université Grenoble Alpes, CNRS)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cancer Therapeutics

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 12305

Abstract: Arry-520 is an advanced drug candidate from the Eg5 inhibitor class undergoing clinical evaluation in patients with relapsed or refractory multiple myeloma. Here we show by structural analysis that Arry-520 binds stoichiometrically to the motor domain of Eg5 in the conventional allosteric loop L5 pocket in a complex that suggests the same structural mechanism as other Eg5 inhibitors. We have previously shown that acquired resistance through mutations in the allosteric binding site located at loop L5 in the Eg5 structure appears to be independent of the inhibitors' scaffold, which suggests that Arry-520 will ultimately have the same fate. When Arry-520 was assessed in two cell lines selected for the expression of either Eg5(D130A) or Eg5(L214A) STLC-resistant alleles, mutations previously shown to convey resistance to this class of inhibitors, it was inactive in both. Surprisingly, when the cells were challenged with ispinesib, another Eg5 inhibitor, the Eg5(D130A) cells were resistant, but those expressing Eg5(L214A) were strikingly sensitive. Molecular dynamics simulations suggest that subtle differences in ligand binding and flexibility in both compound and protein may alter allosteric transmission from the loop L5 site that do not necessarily result in reduced inhibitory activity in mutated Eg5 structures. Whilst we predict that cells challenged with Arry-520 in the clinical setting are likely to acquire resistance through point mutations in the Eg5 binding site, the data for ispinesib suggests that this resistance mechanism is not scaffold independent as previously thought, and new inhibitors can be designed that retain inhibitory activity in these resistant cells.

Journal Keywords: Eg5; mitosis; Arry-520; resistance; multiple myeloma

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 25/09/2019 08:53

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)