Abstract
Background: Even with the prevalent usage of specified treatment protocols, treatment gap remains and besides that the conventional therapies used routinely inflict significant toxicity due to low specificity. Therefore, the development of novel targeted therapies which are active against resistant leukemia subtypes and at the same time offer low toxicity in patients is of high importance. We, therefore, aimed to develop and characterize novel precision compounds, which target oncogene stabilization via HSP90 axis.
Aims: We have previously developed a novel peptidomimetic HSP90 inhibitor (AX) which was active as a pan-leukemia inhibitor against LSCs without inducing any Heat Shock Resoponse (HSR). However due to peptidomimetic nature and high molecular weight, the clinical implication of AX was limited. Therefore, using the previous knowledge we focused on developing second generation of small molecule inhibitor against the C-terminal dimerization of HSP90 with better efficacy and clinical potential.
Methods: We have generated the library of small molecule inhibitor targeting HSP90 C-terminus and selected the most potent analogue (VWK147) depending upon its higher potency against leukemic/cancerous cells. The specificity of VWK147 was further evaluated by microscale thermophoresis (MST), cell-based luciferase refolding assay, 2D NMR spectroscopy, analytical ultracentrifugation and molecular dynamics simulations.
Results: HSP90 act as molecular chaperone and is highly expressed in several therapy-resistant leukemia subtypes thereby ensuring correct protein folding of several oncogenic proteins such as BCR-ABL1, FLT3-ITD and AKT. Therefore, targeting HSP90 could be a promising option in the treatment of therapy-refractory leukemia. Majority of available HSP90 inhibitors target the N-terminal domain thereby induce a protective mechanism called heat shock response (HSR), which potentially weakens the cytotoxic effect of HSP90 inhibitors and induce toxicity. We have now developed first in class small molecule HSP90 C-terminal dimerization inhibitor 'VWK147' through structure-based molecular design and chemical synthesis which specifically targets C-terminal dimerization of HSP90. Like AX, VWK147 destabilizes BCR-ABL oncoprotein and its related pro-oncogenic cellular response (involving proliferation, apoptosis and differentiation), effective in preclinical AML and TKI (2nd and 3rd generation) resistant cell line models in vitro and induces apoptosis in primary AML and BCR-ABL1+ BCP-ALL patient derived leukemic cell, without inducing any HSR. The next step would be to to evaluate its in vivo activity and pharmacodynamic profiling.
Conclusion: Taken together, VWK147 represents a promising next step for future efforts towards the development of novel targeted HSP90 inhibitors to overcome drug resistance and reduce toxicity, especially for the treatment of relapsed/refractory ALL.
References:Bhatia S, Diedrich D, Frieg B, et al. Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response. Blood. 2018;132(3):307-320.John C. Byrd. HSP90 inhibition without heat shock response. Blood commentary 2018. doi: https://doi.org/10.1182/blood-2018-05-850271.
Disclosures
No relevant conflicts of interest to declare.
C-terminal HSP90 Inhibitors Block the HSP90:HIF-1α Interaction and Inhibit the Cellular Hypoxic Response