Abstract 3245: Preclinical evaluation of the imipridone family of small molecules, including analogues of clinical-stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212

The circadian rhythms are an intrinsic timekeeping system that regulates numerous physiological, biochemical, and behavioral processes at intervals of approximately 24 h. By regulating such processes, the circadian rhythm allows organisms to anticipate and adapt to continuously changing environmental conditions. A growing body of evidence shows that disruptions to the circadian rhythm can lead to various disorders, including cancer. Recently, crucial knowledge has arisen regarding the essential features that underlie the overt circadian rhythm and its influence on physiological outputs. This knowledge suggests that specific small molecules can be utilized to control the circadian rhythm. It has been discovered that these small molecules can regulate circadian-clock-related disorders such as metabolic, cardiovascular, inflammatory, as well as cancer. This review examines the potential use of small molecules for developing new drugs, with emphasis placed on recent progress that has been made regarding the identification of small-molecule clock modulators and their potential use in treating cancer.

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Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers

Scientific Reports ◽

10.1038/s41598-021-90801-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Martina Meßner ◽

Melanie M. Mandl ◽

Mathias W. Hackl ◽

Till Reinhardt ◽

Maximilian A. Ardelt ◽

...

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Breast Cancer Cell Lines ◽

Cancer Therapies ◽

Oxygen Species ◽

Transport Chain ◽

Anti Cancer ◽

Major Attention

AbstractThe human mitochondrial ClpXP protease complex (HsClpXP) has recently attracted major attention as a target for novel anti-cancer therapies. Despite its important role in disease progression, the cellular role of HsClpXP is poorly characterized and only few small molecule inhibitors have been reported. Herein, we screened previously established S. aureus ClpXP inhibitors against the related human protease complex and identified potent small molecules against human ClpXP. The hit compounds showed anti-cancer activity in a panoply of leukemia, liver and breast cancer cell lines. We found that the bacterial ClpXP inhibitor 334 impairs the electron transport chain (ETC), enhances the production of mitochondrial reactive oxygen species (mtROS) and thereby promotes protein carbonylation, aberrant proteostasis and apoptosis. In addition, 334 induces cell death in re-isolated patient-derived xenograft (PDX) leukemia cells, potentiates the effect of DNA-damaging cytostatics and re-sensitizes resistant cancers to chemotherapy in non-apoptotic doses.

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Structure-activity relationships (SAR) and mechanistic analysis of clinical-stage anti-cancer small molecule ONC201 analogues.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e23161 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e23161-e23161

Author(s):

Jessica Wagner ◽

Gary Olson ◽

Bhaskara Rao Nallaganchu ◽

Richard Pottorf ◽

Martin Stogniew ◽

...

Keyword(s):

Small Molecule ◽

Clinical Stage ◽

Structure Activity Relationships ◽

Structure Activity ◽

Mechanistic Analysis ◽

Anti Cancer

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Plinabulin, a novel small molecule clinical stage IO agent with anti-cancer activity, to prevent chemo-induced neutropenia and immune related AEs.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.126 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 126-126 ◽

Cited By ~ 6

Author(s):

Ramon W. Mohanlal ◽

Ken LLoyd ◽

Lan Huang

Keyword(s):

Small Molecule ◽

T Cell Activation ◽

Bone Pain ◽

Cell Activation ◽

Clinical Stage ◽

Pde4 Inhibitor ◽

Anticancer Efficacy ◽

Anti Cancer ◽

Anti Inflammatory

126 Background: Plinabulin (Plin) is a small molecule with tumor-inhibiting and immune-enhancing effects by targeting Dendritic Cells (DCs). In preclinical studies, Plin induces DC maturation and the production of MHCII, CD40, CD80 and CD86 and related antigen-specific T-cell activation. Plin had synergistic anticancer efficacy with PD1+CTLA4inhibitors in animal models. In addition, Plin increases expression of IL-1β, IL-6, IL-12 in DC cell, which cytokines protect neutrophils against apoptosis. In a Phase 2 (Ph2) trial, the addition of Plin to Docetaxel (Plin+Doc; n = 38) in NSCLC patients (pts) with a measurable lesion, improved mOS with 4.6 mo vs Doc alone (n = 38). DOR (a marker of immune effect) was ~1 yr longer (P < 0.05) with Plin+Doc vs Doc alone. Plin exerted immune-enhancing effects (DOR), without increasing Immune-Related AEs (IR-AEs). This may suggest that Plin exerts immune-enhancing and anti-inflammatory effects. Methods: Prospective, randomized Ph2 clinical trial (NCT00630110) and non-clinical studies. Results: In-vitro screens showed that Plin is a PDE4-inhibitor, and clinical evidence (p < 0.03; n = 90) of PDE4-inhibition with Plin was observed in Ph2. PDE4-inhibitors have steroid-like effects and are approved for the treatment of Inflammatory disorders, and thus have the potential to prevent IR-AEs. In addition, Plin prevented chemo-induced Neutropenia (CIN), through a mechanism, different from G-CSF, in non-clinical (with various chemotherapies) and Ph2. In Ph2, Gr 4 Neutropenia occurred in 5% with Plin+Doc vs 33 % off pts with Doc (p < 0.0003) in Cycle 1, day 8. Plin is given 30 min after chemo (on the same day of chemo), and does not cause bone pain. G-CSF is given 24 hr after chemo, and causes bone pain in most pts. Conclusions: Plin exerts anticancer immune-enhancing effects, combined with anti-inflammatory effects, due to PDE4-inhibition. Plin holds the promise of an agent with anti-cancer efficacy, while also mitigating IR-AEs and CIN. Therefore, Plin is an attractive candidate for combination therapy with PD1-inhibitors (or PD-L1 inhibitors), PD1+CTLA-inhibitor, or PD1-inhibitor/chemotherapy.

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Small-Molecule Targeted Aβ42 Aggregate Degradation: Negatively Charged Small Molecules Are More Promising than the Neutral Ones

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.1c00047 ◽

2021 ◽

Author(s):

Jinfei Mei ◽

Huijuan Yang ◽

Bo Sun ◽

Chengqiang Liu ◽

Hongqi Ai

Keyword(s):

Small Molecules ◽

Small Molecule

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STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

Neuro-Oncology ◽

10.1093/neuonc/noaa215.837 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii200-ii200

Author(s):

Stephen Skirboll ◽

Natasha Lucki ◽

Genaro Villa ◽

Naja Vergani ◽

Michael Bollong ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Small Molecules ◽

Small Molecule ◽

Large Scale ◽

Critical Role ◽

Tumor Formation ◽

Cell Type ◽

Caspase 1 ◽

Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

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