NIH grant: Second-Generation Stat5 Inhibitors for Prostate Cancer Therapy (1R01CA308805-01A1)

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NIH grant 1R01CA308805-01A1: Second-Generation Stat5 Inhibitors for Prostate Cancer Therapy
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: MARJA T NEVALAINEN. Award: $796727.
Start: 2026-07-17T00:00:00.
PROJECT SUMMARY:
 There is an unmet medical need for potent orally bioavailable pharmacological inhibitors of Stat5a/b (Stat5)
for clinical development. Stat5 is activated in 60% of clinical castrate-resistant (CR) prostate cancers (PC). The
CR state of PC is incurable and results from a failure of androgen-deprivation therapy, which targets androgen
receptor (AR) activity. AR and its splice variants are expressed and persistently active in the majority of the cells in
CRPC tumors. A continuum of focused research has shown that Stat5 is critical for sustaining PC cell viability
and, consequently, blockade of Stat5 signaling inhibits CRPC tumor growth. Our recently published discovery
showed that Stat5 signaling induces transcription of the AR gene in PC, thereby driving mRNA and protein
expression of both full-length AR and its splice variants. We propose that development of Stat5 inhibitory (Stat5-
i) compounds offers a novel therapeutic strategy to suppress AR levels and growth of PC cells. The goal of this
proposal is to generate Stat5-i drug candidate family with a known mechanism of action for clinical development
pipeline. Our lead compound Stat5-i, IST5-002 (IST5), has simple chemical features amenable for chemistry lead
optimization to improve drug-like properties such as metabolic stability, pharmacokinetics and aqueous solubility vs.
lipophilicity. IST5 targets the SH2-domain of Stat5, which blocks its SH2-domain-mediated docking to the
receptor-kinase complex and leads to suppression of Stat5 phosphorylation. The SH2-domain of Stat5 also
mediates dimerization of two Stat5 molecules, which is inhibited by IST5. Importantly, IST5 downregulates AR
gene transcription leading to depletion of AR mRNA and protein levels in PC. IST5 suppression of the AR levels
is associated with extensive PC cell death in vitro, in patient-derived PCs cultured ex vivo and leads to blockade
of PC tumor growth in vivo. IST5 treatment does not cause acute or chronic toxicity in immunocompetent mice
or suppress viability of immune cells. We propose to optimize our IST5 lead compound by structure-based
rational design, synthesis, and potency testing to develop orally active 2nd generation IST5-analog drug-candidate
family with improved metabolic properties, bioavailability and pharmacokinetics for high efficacy in four aims: 1)
Design and synthesize a series of 2nd generation IST5 analogs with improved drug-like properties; 2) Identify the
most promising IST5 analogs and validate their potency and selectivity; 3) Assess the stability, toxicity and
pharmacokinetics of the most promising IST5 analogs; 4) Evaluate the efficacies and pharmacodynamic
properties of the top IST5 analogs to suppress CRPC growth, AR levels and metastatic PC phenotype. The
approach is iterative where Aim 1 is 2-tiered. A set of compounds with specific chemical modifications in the core of
the lead compound structure will be synthesized first, followed by testing in studies in Aims 2-3. Throughout the
study, select compounds will re-enter Aim 1 for further modifications as needed. We expect to develop highly potent
orally available Stat5-i(s) for IND-enabling studies and clinical development for PC therapy.

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