HergenrotherLab/GramNegAccum: Publication v1.0

Open MIND · 2026-04-26

Version of data analysis workflow that accompanies initial publication. Predictive Compound Accumulation Rules Yield a Broad-Spectrum Antibiotic. Richter, M. F.; Drown, B. S.; Riley, A. P.; Garcia, A.; Shirai, T.; Svec, R. L.; Hergenrother, P. J. Nature 2017, published on web May 10, 2017.

HergenrotherLab/GramNegAccum: Publication v1.0

Zenodo (CERN European Organization for Nuclear Research) · 2026-04-26

Version of data analysis workflow that accompanies initial publication. Predictive Compound Accumulation Rules Yield a Broad-Spectrum Antibiotic. Richter, M. F.; Drown, B. S.; Riley, A. P.; Garcia, A.; Shirai, T.; Svec, R. L.; Hergenrother, P. J. Nature 2017, published on web May 10, 2017.

PAC-1 Synergizes with Sunitinib to Enhance Cell Death in Pancreatic Neuroendocrine Tumors

ACS Pharmacology & Translational Science · 2025-04-02 · 1 citations

Pancreatic neuroendocrine tumors (PNETs) are rare tumors that are often diagnosed at advanced or metastatic stages, resulting in a poor prognosis. Sunitinib is an approved therapy for treatment of patients with PNETs, but low response rates and resistance have limited its impact, with autophagy and sunitinib sequestration in the lysosome identified as key resistance mechanisms. Here, we show that the combination of sunitinib with the procaspase-3 activator PAC-1 enhances PNET cell death in cell culture and in vivo in a xenograft tumor model. PAC-1 treatment enlarges lysosomes, resulting in partial lysosomal membrane permeabilization and blocking of autophagosome-lysosome fusion. These alterations lead to increased accumulation of autophagic structures, blocking autophagic flux, and a changed distribution of sunitinib from the lysosome to the cytosol. Our data show that PAC-1 modulates sunitinib-induced autophagy and blocks lysosomal trapping, potentiating sunitinib activity and increasing death of cancer cells. As both drugs are well-tolerated in patients, the data suggest evaluation of the PAC-1/sunitinib combination in a clinical trial of patients with PNET.

Supplementary Data from Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy–Induced Necrosis

2025-11-24

<p>Supplementary Movie 1</p>

BPS2025 - Refining gram-negative antibiotic discovery using AI and molecular simulation

Biophysical Journal · 2025-02-01

Supplementary Data from Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy–Induced Necrosis

2025-11-24

<p>Supplementary Movie 2</p>

Identification of a Selective Anticancer Agent from a Collection of Complex-And-Diverse Compounds Synthesized from Stevioside

Journal of the American Chemical Society · 2025-03-12 · 7 citations

Compounds constructed by distorting the ring systems of natural products serve as a ready source of complex and diverse molecules, useful for a variety of applications. Herein is presented the use of the diterpenoids steviol and isosteviol as starting points for the construction of >50 new compounds through this complexity-to-diversity approach, featuring novel ring system distortions and a noteworthy thallium(III) nitrate (TTN)-mediated ring fusion. Evaluation of this collection identified SteviX4 as a potent and selective anticancer compound, inducing cell death at low nanomolar concentrations against some cancer cell lines in culture, compared to micromolar activity against others. SteviX4 induces ferroptotic cell death in susceptible cell lines, and target identification experiments reveal SteviX4 acts as an inhibitor of glutathione peroxidase 4 (GPX4), a critical protein that protects cancer cells against ferroptosis. In its induction of cell death, SteviX4 displays enhanced cell line selectivity relative to most known GPX4 inhibitors. SteviX4 was used to reveal dependency on GPX4 as a vulnerability of certain cancer cell lines, not tied to any one type of cancer, suggesting GPX4 inhibition as a cancer type-agnostic anticancer strategy. With its high fraction of sp3-hybridized carbons and considerable cell line selectivity and potency, SteviX4 is unique among GPX4 inhibitors, serving as an outstanding probe compound and basis for further translational development.

Supplementary Data from Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy–Induced Necrosis

2025-11-24

<p>Supplementary Movie 3</p>

A necrosis inducer promotes an immunogenic response and destroys ovarian cancers in mouse xenografts and patient ascites organoids

Cancer Letters · 2025-04-29 · 5 citations

Most ovarian cancer patients present with advanced disease and there are few targeted therapies ; consequently, five-year survival for ovarian cancer remains below 50%. We described the anticipatory unfolded protein response (a-UPR) hyperactivator, ErSO, which induced profound and often complete regression of breast cancer in mouse models. Here we explore the effectiveness of ErSO against ovarian cancer. ErSO induced death of human PEO4 and Caov-3 ovarian cancer cells in vitro . In mouse xenografts , injected ErSO induced rapid complete, or near complete, regression of orthotopic metastatic PEO4 tumors and of Caov-3 ovarian tumors . Ovarian cancer patients often develop malignant ascites containing ovarian cancer organoids that drive metastasis . ErSO showed activity against 7/7 fresh patient derived ascites organoids (PDAOs). Low nanomolar ErSO destroyed 2/7 PDAOs. ErSO-mediated cell death in PDAOs occurred through the same a-UPR activation mechanism seen in cell culture. Moreover, ErSO family compound-induced a-UPR activation in ovarian cancer cells triggers necrotic cell death and release of damage associated molecular patterns (DAMPs), which strongly activated human macrophage and induced monocyte migration. These studies suggest ErSO has unusual potential for treatment of advanced ovarian cancer. • ErSO family compounds induce immune-cell-activating necrosis, potentially facilitating immunotherapy for ovarian cancer. • ErSO-induced a-UPR hyperactivation destroys ovarian cancers and is effective in patient-derived ascites organoids. • Rapid assessment of drug sensitivity in fresh ascites organoids facilitates patient selection.

Comparative oncology in action: vignettes on small molecule development

Veterinary oncology. · 2025-04-15 · 1 citations

Abstract Comparative oncology is the study of naturally-occurring cancer in companion (pet) animals, mainly dogs, and is a powerful tool in cancer research and drug development. Comparative oncology clinical trials are defined by their translational value to human cancer research through unique opportunities to evaluate in vivo target modulation, drug tolerability, pharmacokinetic-pharmacodynamic (PK-PD) relationships, and identification of translatable biomarkers for drug response. In this manuscript we review specific examples of how comparative oncology clinical trials, built upon and designed to supplement conventional preclinical datasets, have led directly to human clinical development and eventual approval. In doing so, provide a facile reference for those unfamiliar with canine comparative oncology trials and their link to human cancer drug development, inclusive of their purpose, design elements and data interpretation.