The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

Abstract

A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC 50 values on three of the Hsp90 isoforms (Hsp90a, Hsp90b, and GRP94) and 320 nanomolar IC 50 value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.

TRAP1 regulates cell cycle and apoptosis in thyroid carcinoma cells

“…Consistently, HSP990, which is not engineered to enter mitochondria, significantly inhibited ERK signaling, cell cycle progression and cell proliferation. HSP990 is a TRAP1 inhibitor, as previously demonstrated in other tumor cell models (Menezes et al 2012, Condelli et al 2014 and confirmed in TC cells by the downregulation of specific TRAP1 client proteins. It is also an inhibitor of HSP90 and likely other HSP90 chaperones, as their ATPase domains are highly homologous.…”

“…We recently demonstrated that the dual HSP90/ TRAP1 inhibitor HSP990, that in previous studies was shown to inhibit TRAP1 ATPase domain (Menezes et al 2012), antagonizes TRAP1 chaperoning activity toward its client proteins and acts as cytostatic agent in BRAF-mutated colon carcinoma cells (Condelli et al 2014). Hence, this agent was used to further validate TRAP1 as a potential therapeutic target in TC cells.…”

“…ovarian, cervical and kidney carcinomas) (Yoshida et al 2013, Matassa et al 2016). This issue is relevant in human TC cells since activation of ERK signaling with parallel loss of TSHR signaling and thyroid-specific characters correlates with worsening of clinical outcome (Menezes et al 2012, Regalbuto et al 2012, Patel & Shaha 2014. Interestingly, while the majority of TCs are well-differentiated tumors with excellent prognosis, a subset of TCs are characterized by a more aggressive biological and clinical behavior, unresponsiveness to radioiodine therapy and chemotherapeutics and increased metastatic dissemination (Mazzaferri & Massoll 2002, Regalbuto et al 2012.…”

Evidence for Efficacy of New Hsp90 Inhibitors Revealed by Ex Vivo Culture of Human Prostate Tumors

“…Most Hsp90 inhibitors bind to the conserved ATP pocket of Hsp90, preventing maturation of client proteins and causing their proteasomal degradation. NVP-AUY922 (hereafter called AUY922) and NVP-HSP990 (HSP990) likewise bind to the ATP-binding pocket of Hsp90 and represent 2 of the most potent synthetic small molecule inhibitors reported to date (14,15). AUY922 is a resorcinylic isoxazole amide with antitumor activity against a range of cancer cell lines and animal models, including PC-3 prostate cancer cells and xenografts (14,(16)(17)(18), and in a phase I study in patients with advanced solid malignancies, disease stabilization (16%) was observed (19).…”

“…AUY922 is a resorcinylic isoxazole amide with antitumor activity against a range of cancer cell lines and animal models, including PC-3 prostate cancer cells and xenografts (14,(16)(17)(18), and in a phase I study in patients with advanced solid malignancies, disease stabilization (16%) was observed (19). HSP990 is an orally available aminopyrimidine with antiproliferative activity in a variety of cancer cell lines and xenografts (15,20) and is currently in phase I clinical trials (www.clinicaltrials.gov). Unlike 17-AAG, AUY922 and HSP990 are not susceptible to MDR mechanisms such as P-glycoprotein-mediated efflux or polymorphic metabolism by the enzyme NQO1/DT-diaphorase (14,15).…”