Biology subjects

Samajdar, S.

Publications and source records attributed to Samajdar, S..

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↗

bioRxiv2026

A highly stringent high-throughput screening assay for identifying transcription-modulating agents of HIV-1 latency

HIV-1 latency remains a central obstacle to curing infection, and current latency-modulating agents (LMAs) suffer from poor specificity and inconsistent efficacy. To enable discovery of small molecules (SMs) that directly target the viral master transcriptional regulatory circuit (MTRC), we developed a highly stringent, dual-reporter high-throughput screening (HTS) assay based on a natural HIV-1 subtype C long terminal repeat (LTR) variant, LRhR-HC, which exhibits markedly reduced transcriptional noise and a high activation threshold. We engineered Jurkat cells to stably harbour two independent reporter cassettes driven by the tough-to-activate LRhR-HC-LTR and the canonical LR-HHC-LTR, enabling simultaneous detection of latency-promoting and latency-reversing activities through both fluorescent and secreted enzymatic reporters. This dual-reporter line responded robustly and predictably to conventional latency-reversal agents (LRAs) and latency-promoting agents (LPAs), validating assay responsiveness. Z'-factor measurements demonstrated excellent assay performance, with values ranging from approximately 0.7 across different formats, confirming a strong dynamic range and reproducibility. Screening of the 1,520-compound Prestwick chemical library (PCL), which includes FDA-approved drugs, identified 27 candidate LPAs, including known agents such as Spironolactone and Aminacrine, thereby validating the assay specificity while revealing several novel inhibitory molecules. A mechanistically focused panel of 10 additional compounds yielded two putative LPAs and one LRA, with secondary analyses confirming their latency-modulating activities and cytotoxicity profiles. Collectively, this HIV-1C-derived dual-reporter platform provides a stringent and flexible HTS system for identifying LMAs with potential applications in both block-and-lock and shock-and-kill cure strategies.

molecular 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

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↗