Structure‐Based Design, Synthesis, and Biological Evaluation of Hsp90β‐Selective Inhibitors

Abstract

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that are responsible for the folding and/or trafficking of ~400 client proteins, many of which are directly associated with cancer progression. Consequently, inhibition of Hsp90 can exhibit similar activity as combination therapy as multiple signaling nodes can be targeted simultaneously. In fact, seventeen small-molecule inhibitors that bind the Hsp90 N-terminus entered clinical trials for the treatment of cancer, all of which exhibited pan-inhibitory activity against all four Hsp90 isoforms. Unfortunately, most demonstrated undesired effects alongside induction of the pro-survival heat shock response. As a result, isoform-selective inhibitors have been sought to overcome these detriments. Described herein is a structure-based approach to design Hsp90β-selective inhibitors along with preliminary SAR. In the end, compound 5 was shown to manifest ~370-fold selectivity for Hsp90β versus Hsp90α, and induced the degradation of select Hsp90β-dependent clients. These data support the development of Hsp90β-selective inhibitors as a new paradigm to overcome the detriments associated with pan-inhibition of Hsp90.

Radiosynthesis and preclinical evaluation of [11C]SNX-ab as an Hsp90α,β isoform-selective PET probe for in vivo brain and tumour imaging

“…Additionally, novel approaches for Hsp90 targeted therapy intend to avoid harmful side effects associated with pan-inhibition by using non-traditional modulation of Hsp90, including C-terminal inhibition or isoform-selective inhibition. The research group of Blagg has recently made a major contribution to this research area by developing several new isoform-selective inhibitors (Chaudhury et al 2021 ; Crowley et al 2017 , 2016 ; Khandelwal et al 2018 , 2017 ; Mishra et al 2021a , 2021b , 2017 ; Muth et al 2014 ), including the more challenging development of Hsp90α (Mishra et al 2021a ) and Hsp90β (Chaudhury et al 2021 ; Khandelwal et al 2018 ; Mishra et al 2021b ) selective compounds. Their Hsp90β-selective inhibitors were claimed to be cytotoxic to cancer cells while not inducing a HSR, thereby overcoming the detriments associated with pan-Hsp90 inhibition (Mishra et al 2021b ).…”

HSP90 mediates the connection of multiple programmed cell death in diseases

“…So, the researches on isoform-selective inhibitors are still continually deepened, which is conductive to reducing the pan-inhibition of Hsp90. In the study of Chaudhury et al, the reported complex shows the greatest selectivity towards HSP90β, and even more than 370 fold compared with HSP90α [ 143 ]. In general, although the problems of targeting HSP90 in disease treatment have revealed, it still be a feasible approach because these problems could be gradually solved.…”

Heat shock protein 90: biological functions, diseases, and therapeutic targets

“…124 To date, a roster of over 400 known HSP90 client proteins has been assembled, most of which are oncogene products or key regulators of signal transduction pathways, significantly promoting the initiation and progression of cancer. 125 Furthermore, the progression of cancer heavily relies on essential signaling pathways, each prominently featuring key oncoproteins recognized as HSP90 clients (Figure 3). For instance, the signaling cascade of TGF-β plays a critical role in governing various cellular processes, including cell proliferation, differentiation, apoptosis, and migration.…”