Biology subjects

Abbineni, C.

Publications and source records attributed to Abbineni, C..

4 recordsLinked to original sources

bioRxiv2026

A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity

Many cancers evade immunity by converting neutrophils into polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), but the chromatin mechanisms that maintain this pathological state remain unclear. Here we show that tumor-induced suppressive neutrophils depend on mSWI/SNF chromatin remodeling. Two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, produced immune-dependent tumor control across syngeneic models, including tumors resistant to PD-1 blockade, and enhanced checkpoint therapy without overt toxicity. Treatment rapidly depleted intratumoral PMN-MDSCs, restored functional CD8+ T cells, and blocked tumor explant-induced expansion and suppressive activity of mouse and human PMN-MDSCs. mSWI/SNF antagonism collapsed chromatin accessibility and PU.1/C/EBP{beta} occupancy at regulatory elements that sustain PMN-MDSC identity. Thus, suppressive neutrophils harbor a druggable chromatin vulnerability that can be exploited to restore cancer immunity.

cancer biology↗

bioRxiv2025

SynGlue: AI-Driven Designer for Clinically Actionable Multi-Target Therapeutics

The rational design of protein degraders, such as proteolysis-targeting chimeras (PROTACs), requires the simultaneous optimization of multiple molecular properties, a complex challenge that limits efficient discovery. Here, we introduce SynGlue, a generative artificial intelligence (AI) framework that addresses this challenge through two core modules: data-driven, leveraging large-scale protein-ligand intelligence, and structure-guided, for physics-aware molecular design. SynGlue harness MagnetDB, a curated database of 6.37 million experimental protein-ligand interactions, and couples it with deep learning models that quantitatively predict degradation potency (DC50), maximal degradation (Dmax), and guide ternary-complex-compatible linker design. Benchmarked against 6,935 compounds, SynGlue demonstrates superior performance in relevant pharmacology prediction. To validate SynGlue, we engineered degraders for BRD4 and GSPT1. Our data-driven design for BRD4 yielded compounds with novel warhead scaffolds (<50% warhead similarity with known PROTACs), which proved to be potent degraders in vitro (DC50 = 0.19 nM) and efficacious in vivo in mouse models. Independently, our structure-guided de novo design for GSPT1 produced ultrapotent degraders (DC50 {approx} 0.0011 M) that are also effective both in vitro and in vivo, uncovering a new oncogenic dependency. By unifying data-driven and physics-aware design, SynGlue establishes a generalizable AI framework for the rapid development of clinically relevant protein degraders, with principled extension to other multi-target modalities.

bioinformatics↗

bioRxiv2024

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer

Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 (BRD4) and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise. Significance StatementThe mSWI/SNF complex is a promising therapeutic target for enhancer-driven cancers. PROTACs, which enable the targeting of "undruggable" proteins, often face the challenge of achieving oral bioavailability. Here, we present AU-24118, a first-in-class, orally bioavailable mSWI/SNF ATPase dual degrader with remarkable efficacy in in vitro and in vivo models. Additionally, our study describes two distinct mechanisms of resistance to PROTAC degraders, providing crucial insights into potential challenges facing their clinical application. These findings are critical for advancing PROTAC-based therapies to clinical settings as targeted therapies for cancers.

cancer biology↗

bioRxiv2024

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies

The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

cancer biology↗