Heat shock factor 1 (HSF1) is a key regulator of the heat shock response. Especially, HSF1 plays an important role in various cancers. In this study, researchers described the identification of a direct HSF1 inhibitor, Direct Targeted HSF1 Inhibitor (DTHIB).

DTHIB physically engages HSF1 and selectively stimulates the degradation of nuclear HSF1. Moreover, DTHIB strongly inhibits the HSF1 cancer gene signature and prostate cancer cell proliferation. In addition, DTHIB potently attenuates tumor progression in four therapy-resistant prostate cancer animal models. DTHIB physically binds to the HSF1 DBD with a dissociation constant (Kd) of 160 nM. In mouse embryonic fibroblasts (MEFs), DTHIB attenuates the robust acute heat shock induction of the HSP70 and HSP25 molecular chaperones.

DTHIB reduces nuclear HSF1 steady-state protein abundance in a dose-dependent manner. DTHIB treatment of C4-2 PCa cells depletes androgen receptor (AR) protein and potently dampens expression of the AR target gene KLK3. In 22Rv1 cells, DTHIB inhibits HSF1 and leads to the coordinated depletion of molecular chaperones including HSP40 and HSP70. Similarly, in C4-2 cells, DTHIB exhibits superior efficacy in the inhibition of AR signaling and cell growth. Besides, DTHIB attenuates AR and AR-v7 signaling in 22Rv1 cells. In clonogenic assays, DTHIB dose-dependently reduces the clonal expansion of both C4-2 and PC-3 PCa cells.

DTHIB prevents tumor growth in multiple therapy-resistant PCa models and inhibits the HSF1 CaSig in human tumor cells implanted in mice. Furthermore, DTHIB is well tolerated in animals at doses of as high as 25 mg/kg per day.

Together, DTHIB inhibits HSF1 by preferentially stimulating nuclear HSF1 degradation via a proteasome- and FBXW7-dependent pathway while sparing other targets of this degradation pathway.

Bushu Dong, et al. Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1. Sci Transl Med. 2020 Dec 16;12(574):eabb5647.