Development of a First-in-Class Small Molecule Inhibitor of the C-terminal Hsp90 Dimerization

17 December 2021, Version 1


Heat shock protein 90 (Hsp90) is a promising therapeutic target due to its involvement in stabilizing several aberrantly expressed oncoproteins. In cancerous cells, Hsp90 expression is elevated, thereby contributing in exerting anti-apoptotic effects, which is essential for the malignant transformation and progression of several tumor types. Most of the Hsp90 inhibitors (Hsp90i) under investigation target the ATP binding site in the N-terminal domain (NTD) of Hsp90. However, adverse effects, including induction of the pro-survival resistance mechanism (heat shock response or HSR) and associated dose-limiting toxicity, have so far precluded clinical approval of these Hsp90i. In contrast, modulators that interfere with the C-terminal domain (CTD) of Hsp90 do not inflict HSR and, thus, emerge as a promising alternative approach to target Hsp90. Since the CTD dimerization of Hsp90 is essential for its chaperone activity, interfering with this essential dimerization process by small-molecule protein-protein interaction (PPI) inhibitors is a promising strategy for anticancer drug research. We have developed the first-in-class small molecule inhibitor (5b) targeting the Hsp90 CTD dimerization interface, based on a tripyrimidonamide scaffold through structure-based molecular design, chemical synthesis, binding mode model prediction, assessment of the biochemical affinity and efficacy against therapy-resistant leukemia cells. 5b reduces xenotransplantation of leukemia cells in zebrafish models and induces apoptosis in BCR-ABL1+ (T315I) tyrosine kinase inhibitors (TKIs) resistant leukemia cells, without inducing HSR.


Protein-protein interaction inhibitor
Heat shock response

Supplementary materials

Supplementary Note 1 and 2
- See Supplementary Note 1 for Chemical Synthesis (including general methods, synthetic protocols, compound characterization, and spectral data - SI Figure 1 - 20) and supplementary figures (SI Figure 21-31) and supplementary table (SI Table 1-2) - See Supplementary Note 2 for Physicochemical properties of 5b


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