Unraveling the Efficacy of AR Antagonists Bearing N-(4-(Benzyloxy)phenyl)piperidine-1-sulfonamide Scaffold in Prostate Cancer Therapy by Targeting LBP Mutations.

Design, synthesis and anti-glioblastoma multiforme activity of N-methoxy-2-(pyrimidin-4-ylamino)benzamide derivatives as focal adhesion kinase inhibitors.

Abstract IA02: Direct targeting of the intrinsically disordered transactivation domain of androgen receptor enables transcriptome-selective pharmacology

Androgen receptor (AR) is a therapeutic target for prostate cancer. Despite effective drugging its folded ligand-binding domain (LBD), resistance will develop by mechanisms involving reactivation of AR signaling. These mechanisms include expression of constitutively active AR that lacks LBD such as AR-V7 which fueled the discovery of inhibitors that bind to AR's N-terminal intrinsically disordered transactivation domain (TAD). AR-TAD inhibitors (ARTADIs) are unique due to the paucity of small molecule inhibitors that bind directly to intrinsically disordered TADs, which have historically been considered undruggable. Several ARTADIs have been tested in first-in human clinical trials with acceptable safety and have shown proof-of-concept for the scaffold. Over 20 years we have designed, synthesized and empirically tested over 500 ARTADIs. Leveraging this proprietary platform using cultured prostate cancer cells and multiple xenograft models we demonstrate that subtle changes in the chemical scaffold produce distinct pharmacological outputs that extend beyond binary AR antagonism. Transcriptomic analyses revealed that individual ARTADIs differentially regulate subsets of AR-responsive genes, including both androgen-induced and androgen-repressed programs, resulting in compound-specific remodeling of the AR transcriptome and signaling pathways implicated in tumor progression. These findings support a model of transcriptome-selective pharmacology. Mechanistically, these compounds differentially disrupt interactions between full-length AR or splice-variant AR-V7, and co-regulators, as revealed by rapid immunoprecipitation mass spectrometry of endogenous protein and the proximity ligation assay. This is suggestive that minor alterations in the chemical structure of ARTADIs stabilize distinct AR-TAD conformational ensembles that drive selective cofactor engagement and downstream transcriptional programs. Biophysically, several ARTADIs exhibited picomolar-to-low-nanomolar dissociation constants and covalent binding to cysteine 129. This demonstrates that intrinsically disordered transactivation domains can be targeted with affinities comparable to, or exceeding, those achieved by the LBD inhibitor enzalutamide. In vivo, representative ARTADIs outperformed enzalutamide against prostate cancer xenografts in the presence of androgens, underscoring the therapeutic potential of targeting alternative AR domains. Collectively, these findings support the concept that direct targeting of the intrinsically disordered AR-TAD enables transcriptome-selective pharmacology, providing a mechanistic framework and a novel therapeutic strategy that may complement conventional AR-directed therapies. Marianne D. Sadar. Direct targeting of the intrinsically disordered transactivation domain of androgen receptor enables transcriptome-selective pharmacology [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr IA02.

Abstract B077: EMI-1725 Demonstrates Broad Antagonist Activity Against Drug-Resistant Androgen Receptor Mutations and Tumor Growth Suppression in Preclinical Models of Metastatic Castration-Resistant Prostate Cancer

Metastatic castration-resistant prostate cancer (mCRPC) remains a leading cause of cancer-related mortality in men, with over 35,000 deaths annually in the United States and a 5-year survival rate of approximately 30%. Although AR-targeted therapies such as enzalutamide and darolutamide delay disease progression, resistance inevitably emerges, underscoring a critical unmet need for next-generation therapeutics. Here, we describe EMI-1725, a novel androgen receptor (AR) antagonist developed to overcome resistance-associated AR mutations. EMI-1725 binds the AR ligand-binding domain with affinities comparable to or higher than enzalutamide and darolutamide. In cell-based transcriptional assays, both enantiomers inhibit wild-type AR activity at potencies comparable to approved agents and retain activity against the most prevalent AR mutation T878A, where EMI-1725 is approximately 5-fold more potent than darolutamide. Critically, EMI-1725 also demonstrates antagonist activity against the enzalutamide-resistant double mutant AR F877L/T878A, a target not addressed by current therapies. In cell viability assays, EMI-1725 inhibits proliferation of two prostate cancer models (AR-amplified VCaP and LNCaP cells expressing the AR T878A mutation). In an AR-amplified xenograft model of mCRPC (VCaP), EMI-1725 reduced tumor growth as well as enzalutamide and suppressed PSA levels below those achieved with enzalutamide at standard dosing. Treatment across all groups was well tolerated over 47 days of daily oral gavage, with no significant weight loss. EMI-1725 showed improved biodistribution across organs, and importantly, displayed less accumulation in the brain compared to enzalutamide, where off-target binding leads to risk of seizure. Collectively, these in vitro and in vivo findings support the advancement of EMI-1725 as a promising therapeutic candidate for mCRPC. Steven Kregel, Raymond J. Kostlan, John T. Phoenix, Audris Budreika, Carleen D. Deegan, Jonathan Katz, Jerry S.H. Lee, Charles McKenna, David B. Agus, Katherin Patsch. EMI-1725 Demonstrates Broad Antagonist Activity Against Drug-Resistant Androgen Receptor Mutations and Tumor Growth Suppression in Preclinical Models of Metastatic Castration-Resistant Prostate Cancer [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B077.

Prenylated 4-Hydroxycoumarin derivatives as inducers of CDK4/6-mediated cell cycle arrest: From design and synthesis to in vitro and in vivo evaluation of their anti-breast Cancer activity.

Breast cancer is the most frequently diagnosed malignancy in women, and safer, more effective therapies are urgently needed. Inspired by the prenylated coumarin scaffolds of Ferulin C and Miliusol, we rationally designed and synthesized a series of novel 4-hydroxycoumarin derivatives (A, B, and PB series) to develop potent anti-breast cancer agents. Among them, lead compound PB1-3 (7-methoxy, geranyl-substituted) exhibited the most potent antiproliferative activity against MCF-7 (IC₅₀ = 3.13 μM) and 4 T1 (IC₅₀ = 4.28 μM) cells, with high selectivity over normal cells. Structure-activity relationship (SAR) analysis underscored that the combination of a methoxy group and an extended geranyl side chain is crucial for activity. Integrated computational studies (molecular docking, 100 ns MD simulations, and MM-PBSA) confirmed that PB1-3 establishes stable hydrogen-bond and hydrophobic interactions with CDK4/6. Mechanistically, PB1-3 functions as a dual-acting CDK4/6 pathway modulator: it not only directly binds to CDK4/6 but, notably, downregulates their total protein expression, thereby reducing Rb phosphorylation and inducing G0/G1 phase arrest. Concurrently, PB1-3 triggers a potent ROS burst, collapses mitochondrial membrane potential (MMP), upregulates the Bax/Bcl-2 ratio, and activates cleaved caspase-3, driving the intrinsic apoptotic cascade. In a 4 T1 orthotopic syngeneic model, PB1-3 (20 mg/kg, i.p.) significantly suppressed tumor growth comparable to cisplatin, while exhibiting excellent biosafety (LD₅₀ > 2000 mg/kg, no hepatotoxicity/nephrotoxicity) and acceptable oral pharmacokinetics (T₁/₂ = 3.0 h). Collectively, PB1-3 represents a promising prenylated coumarin lead that orchestrates both CDK4/6-Rb cell cycle checkpoint blockade and ROS-dependent mitochondrial apoptosis, offering a valuable scaffold for developing targeted breast cancer therapies, especially for TNBC.

Discovery of novel cereblon-recruiting PRMT5 degraders with in vivo efficacy against triple-negative breast cancer.

The epigenetic regulator protein arginine methyltransferase 5 (PRMT5) is aberrantly overexpressed in triple-negative breast cancer (TNBC) and represents a promising therapeutic target. Currently reported PRMT5-targeting PROTAC degraders (MS4322 and MS115) are both derived from a tetrahydroisoquinoline scaffold. These compounds require treatment for more than five days to exert effective antiproliferative activities, and no in vivo antitumor efficacy has been reported. To address these limitations, we adopted the carbazole-based PRMT5 inhibitor PJ-68, which features a lower molecular weight and a more accessible linker attachment site. Herein, we reported a series of novel PRMT5 degraders with carbazole scaffold. The representative compound YZ-17 degraded PRMT5 (DC50 = 2.2 μM in HCC1806 and 3.3 μM in HCC1937 cells) and its adaptor protein MEP50 (DC50 = 2.0 μM and 2.9 μM, respectively) within 24 h. YZ-17 also suppressed PRMT5-mediated symmetric dimethylarginine (sDMA) modification and colony formation, induced G1 phase cell cycle arrest, and displayed favorable antiproliferative activities across several TNBC cell lines (IC50 = 2.6 - 3.7 μM). Importantly, YZ-17 showed in vivo efficacy in an HCC1806 xenograft model, achieving a tumor growth inhibition (TGI) of 44.12% at 30 mg/kg (i.p., every other day) without obvious toxicity. Collectively, YZ-17 represents a structurally novel PRMT5 degrader with rapid onset of action, effective in vitro and in vivo anti-TNBC activity, offering a distinct chemical tool for further functional studies of PRMT5.

Discovery of Potent EGFR Inhibitors for Del19 and L858R/T790M Mutants Through Structure‐Based Virtual Screening and Biological Evaluation

ABSTRACT Epidermal growth factor receptor (EGFR) mutation‐mediated drug resistance represents a major clinical challenge in the treatment of non‐small cell lung cancer (NSCLC). In this study, the lead compound XJ2‐2 was identified through structure‐based virtual screening. It exhibited potent anti‐proliferative activity against both EGFRDel19 mutant PC‐9 cells and EGFRL858R/T790M mutant H1975 cells, with IC50 values of 0.88 ± 0.12 μM and 0.77 ± 0.09 μM, respectively. Mechanistic studies have demonstrated that XJ2‐2 directly targets and binds to the EGFR, thereby effectively inhibiting EGFR phosphorylation and its downstream signaling pathways in both in vitro and in vivo models. In tumor‐bearing mouse models, XJ2‐2 significantly reduced tumor burden. Preclinical safety evaluation indicated that no treatment‐related toxicity was observed for XJ2‐2 at all tested doses. With its novel molecular scaffold and mutant‐selective inhibitory profile, XJ2‐2 represents a promising lead compound for overcoming NSCLC drug resistance and advancing the development of next‐generation EGFR inhibitors.