Baltimore-based Isoprene Pharmaceuticals, Inc. has received a USD 1.02 million NCI SBIR R44 grant to complete IND-enabling preclinical studies for VNPP433-3β, an orally bioavailable small molecule degrader targeting both androgen receptor splice variants and the Mnk1/2-eIF4E translation initiation pathway in prostate cancer.
The award is a Direct-to-Phase II SBIR continuation, reflecting prior completion of Phase I-equivalent work. The NCI's decision to fund IND-enabling activities signals confidence in the preclinical package assembled to date, which includes xenograft efficacy data against the enzalutamide (Xtandi)-resistant CWR22Rv1 model.
VNPP433-3β functions as a molecular glue degrader, inducing ubiquitin-mediated proteasomal degradation of full-length androgen receptor and its splice variants — including AR-V7, a well-validated resistance driver — while simultaneously degrading Mnk1/2 kinases, which regulate cap-dependent translation through eIF4E. Simultaneous suppression of both pathways is intended to limit the compensatory signaling that undermines single-target androgen receptor therapies. Preclinical data reported by the company indicated four-fold enhanced potency for hydrochloride salt forms of the compound against CWR22Rv1 xenografts, with no apparent host toxicity, and activity superior to both enzalutamide and docetaxel (Taxotere) in those models.
The funded work covers three aims: synthesis of 500 g of non-GMP material for formulation and salt-form selection; ancillary pharmacology in prostate cancer in vitro and in vivo models; and GLP toxicology and toxicokinetics in two animal species to support an IND filing and define a starting dose for first-in-human Phase I trials. Principal investigators are Vincent Njar and Vidya P. Ramamurthy.