Biology subjects

Mallesh, S.

Publications and source records attributed to Mallesh, S..

4 recordsLinked to original sources

bioRxiv2025

Structure-Activity-Relationship Exploration and Animal Validation of Novel Assembly Modulator Small Molecule Chemical Series with Pan-Cancer Selective Cytotoxicity

PAV-620, and PAV-805 are chemical analogs from a protein assembly modulating small molecule lead series that displays broad anti-cancer activity. These compounds are active against all cancers in the NCI-60 cancer cell line screen, which is representative of diverse blood, brain, breast, colon, lung, ovarian, prostate, renal, and skin cancers. Safety in mice is observed up to doses of 10 mg/kg daily and nontoxicity to healthy human peripheral blood mononuclear cells at doses up to 20uM. The compounds are as efficacious as Paclitaxel in reducing tumor growth and metastasis in the aggressive 4T1 mouse allograft model for triple negative breast cancer. The mechanism of action of PAV-620 and PAV-805 in primary carcinoma cells under conditions inducing programmed cell death was found to be distinct from the cytotoxic mechanisms of Staurosporine, Paclitaxel, and Etoposide. PAV-805 was shown to target a small subset of protein disulfide isomerase (PDI) in a dynamic multi-protein complex enriched in the cancer hallmark proteins involved in reprogramming energy metabolism. These data suggest a new approach to cancer therapeutics, with selectivity arising not from targeting PDI itself, an abundant cellular protein, but from targeting a disease-associated assembly state of PDI-containing complexes as a therapeutically exploitable dimension of cancer biology.

biochemistry↗

bioRxiv2023

Protein Assembly Modulation: A New Approach to ALS Therapeutics

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with a complex, multifactorial pathophysiology, most commonly manifest as loss of motor neurons. We introduce a new mechanism of ALS pathogenesis via a novel drug-like small molecule series that targets protein disulfide isomerase (PDI) within a previously unappreciated transient and energy-dependent multi-protein complex. This novel drug was found to have activity in cellular models for both familial and sporadic ALS, as well as in transgenic worms, flies, and mice bearing a diversity of human genes with ALS-associated mutations. These compounds were initially identified as modulators of human immunodeficiency virus (HIV) capsid assembly in cell-free protein synthesis and assembly (CFPSA) systems, with demonstrated antiviral activity in cell culture. Their advancement as ALS-therapeutics, and the subsequent separation of activity against HIV and ALS in chemical subseries through structure-activity-relationship optimization, may provide insights into the molecular mechanisms governing pathophysiology of disordered homeostasis relevant to ALS.

neuroscience↗

bioRxiv2022

Small Molecule Assembly Modulators with Pan-Cancer Therapeutic Efficacy

Two structurally-unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951 with antiviral activity in cell culture against monkeypox virus (MPXV) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity, reasonable pharmacokinetics, and non-toxicity in mice at active concentrations. Anti-tumor properties of both chemotypes, were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex containing the protein TRIM28/KAP1, an allosteric modulator known to regulate mechanisms underlying viral and nonviral disease states including cancer. Treatment with these compounds alters the target multi-protein complexes in a manner consistent with allosteric modulation as their mechanism of action. These compounds appear to remove a block, crucial for cancer survival and progression, on the homeostatic linkage of uncontrolled cellular proliferation to apoptosis. These compounds provide starting points for development of next-generation non-toxic, pan-cancer therapeutics.

cancer biology↗

bioRxiv2021

From COVID-19 to the Common Cold: Novel Host-Targeted, Pan-Respiratory Antiviral Small Molecule Therapeutics

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious virus in multiple cell culture models for all six families of viruses causing most respiratory disease in humans. In animals this chemotype has been demonstrated efficacious for Porcine Epidemic Diarrhea Virus (a coronavirus) and Respiratory Syncytial Virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral lifecycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.

biochemistry↗