Novel Hsp90 inhibitors as leads for the development of radiotheragnostics for Meitner-Auger electron therapy

Radiotheragnostics is a promising but still developing approach for Cancer diagnosis and treatment, limited by the availability of high-affinity, targetable proteins. One such target is the 90 kDa heat shock protein (HSP90), a chaperone essential for protein folding and stabilization. Cancer cells rely heavily on HSP90, and its inhibitors show tumor-selective retention. Onalespib (AT13387), a potent HSP90 Inhibitor in phase III clinical trials, was used as a reference for the design of new compounds harbouring atoms with potential for radiotheragnostics. We synthesized 10 Onalespib analogues, modifying the isopropyl group on the resorcinol moiety with bulky atoms like bromine and iodine to mimic its steric effects. The piperazine ring was also substituted with chiral scaffolds using R/S quinuclidine and R/S piperidine to assess the influence of stereochemistry on biological activity. Binding assays showed that non-chiral compounds 12 and 17 had the lowest affinity for HSP90, while R-stereochemistry analogues 16 and 21 had the highest. Brominated analogues 17, 20, and 21 exhibited strong disruption of HSP90 client signaling in cell-based assays. Microscopy confirmed that the new compounds did not alter HSP90 localization. Our preliminary Structure-Activity Relationship (SAR) study, indicates the following. First, the substitution of the isopropyl group with iodine or bromine preserves HSP90 inhibitory function. Second, R-stereochemistry in these compounds plays a key role in the affinity for HSP90. Finally, less bulky substituents (i.e. bromine) have stronger HSP90 inhibition properties than more bulky ones (i.e. iodine). Compound 21, in particular, emerged as a lead compound and will be radiolabeled with ^76/77Br as a radiotheragnostic agent for PET imaging (⁷⁶Br) and Meitner-Auger electron therapy (⁷⁷Br).

Bromine; Cancer; Hsp90; Iodine; Meitner-auger electron therapy; Radiotheragnostics.