Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer

Abstract

Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that are more difficult to treat nearly always occur due to aberrant reactivation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth-inhibitory effects of reengineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A, which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small-molecule activators of PP2A (SMAP) decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable with enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment. A novel class of small-molecule activators of the tumor suppressor PP2A, a serine/threonine phosphatase that inhibits many oncogenic signaling pathways, is shown to deregulate the phosphoproteome and to destabilize the androgen receptor in advanced prostate cancer. .

Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

“…Considering the potential future development of DBK-1154 derivatives for GB therapy, DBK-1154 was evaluated in an acute rat pilot (non-GLP) toxicology study at doses up to 800 mg/kg daily. Consistently with previous SMAP in vivo studies (Sangodkar et al, 2017;McClinch et al, 2018), no significant body weight loss, deaths, or adverse behavioral or neurological effects were observed. The major morphologic finding was hepatocellular hypertrophy (panlobular) in all test article-treated groups, with increased severity as the dose level increased.…”

“…In addition to their different in vivo brain penetrance properties, NZ-8-061 seems to have cytostatic effects at the doses tested, whereas DBK-1154 most probably induces both, decreased proliferation and cell death. On the other hand, a SMAP derivative DBK-766 defective in PP2A reactivation (Sangodkar et al, 2017;McClinch et al, 2018), failed to suppress GB cell viability. The intracellular pathways involved in the apoptosis induction by DBK-1154 in vitro were not addressed in this concise communication, but clearly remains as an important future question to be addressed.…”

“…1A) would compromise BBB permeability, and eventually CNS availability, of the SMAPs as compared to tricyclics. We therefore started by investigating the in vitro BBB passage of NZ-8-061 (a.k.a DT-061) that has been widely used in cancers outside the CNS (Sangodkar et al, 2017;McClinch et al, 2018). Quantified by HPLC-MS/MS, NZ-8-061 was found to cross the artificial BBB (Le Joncour et al, 2019), consisting of murine brain microcapillary endothelial cells and astrocytes ( Fig.…”

“…As a pharmacologic control, U87MG, U118, or A172 cells were also treated with increasing doses of TRC-766, a structurally similar but biologically inactive derivate of SMAPs ( Supplementary Fig. 3A) (Sangodkar et al, 2017;McClinch et al, 2018).…”

Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

“…In accordance with the major theme of this review, a recent study demonstrated that combination of SET targeting and tyrosine kinase inhibitor provides an effective therapeutic approach in human T‐cell acute lymphoblastic leukemia . Apart of small‐molecules targeting the PIPs, the novel series of orally bioavailable and nontoxic PP2A reactivator molecules with profound in vivo therapeutic activities in KRAS mutant lung cancers and castration‐resistant prostate cancer , provide a very encouraging example that PP2A indeed is druggable . In the context of this review, these small‐molecule PP2A activators were recently shown to transform the cytostatic MEK inhibitor responses to cytotoxic, and to greatly promote in vivo therapeutic effects of MEK inhibitor AZD6244 in two KRAS mutant lung cancer xenograft models .…”