Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging.

There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases.

Senolytic treatment alleviates doxorubicin-induced chemobrain.

Doxorubicin (Dox), a widely used treatment for cancer, can result in chemotherapy-induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging.

Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies.

KRAS, a predominant member of the RAS family, is the most frequently mutated oncogene in human pancreatic cancer (∼95% of cases). Mutations in KRAS lead to its constitutive activation and activation of its downstream signaling pathways such as RAF/MEK/ERK and PI3K/AKT/mTOR that promote cell proliferation and provide apoptosis evasion capabilities to cancer cells. KRAS had been considered 'undruggable' until the discovery of the first covalent inhibitor targeting the G12C mutation.

Effect of peripheral cellular senescence on brain aging and cognitive decline.

We examine similar and differential effects of two senolytic treatments, ABT-263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT-263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood-brain barrier (BBB) integrity, and prevented the age-related decline in hippocampal N-methyl-D-aspartate receptor (NMDAR) function associated with impaired cognition.

Co-targeting BCL-X and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice.

Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. The dismal prognosis in SCLC is in part associated with an upregulation of BCL-2 family anti-apoptotic proteins, including BCL-X and MCL-1. Unfortunately, the currently available inhibitors of BCL-2 family anti-apoptotic proteins, except BCL-2 inhibitors, are not clinically relevant because of various on-target toxicities.

Nanovesicle and extracellular polymeric substance synthesis from the remediation of heavy metal ions from soil.

Heavy metal toxicity affects aquatic plants and animals, disturbing biodiversity and ecological balance causing bioaccumulation of heavy metals. Industrialization and urbanization are inevitable in modern-day life, and control and detoxification methods need to be accorded to meet the hazardous environment. Microorganisms and plants have been widely used in the bioremediation of heavy metals.

BCL-X PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRAS-mutated cancers.

KRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRAS, was recently approved for the treatment of KRAS-mutated non-small cell lung cancer (NSCLC). However, the efficacy of sotorasib and other KRAS inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated tumors.

Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-X-Specific Degrader DT2216.

Pancreatic cancer is the third most common cause of cancer-related deaths in the United States. Although gemcitabine is the standard of care for most patients with pancreatic cancer, its efficacy is limited by the development of resistance. This resistance may be attributable to the evasion of apoptosis caused by the overexpression of BCL-2 family antiapoptotic proteins.

Cellular senescence in lymphoid organs and immunosenescence.

Immunosenescence is a multi-faceted phenomenon at the root of age-associated immune dysfunction. It can lead to an array of pathological conditions, including but not limited to a decreased capability to surveil and clear senescent cells (SnCs) and cancerous cells, an increased autoimmune responses leading to tissue damage, a reduced ability to tackle pathogens, and a decreased competence to illicit a robust response to vaccination. Cellular senescence is a phenomenon by which oncogene-activated, stressed or damaged cells undergo a stable cell cycle arrest.

Senescence-associated hyper-activation to inflammatory stimuli .

Aging is associated with an increased susceptibility to adverse inflammatory conditions such as sepsis and cytokine storm. We hypothesized that senescent cells (SnCs) play a central role in this age-associated pathology in part due to their expression of the senescence-associated secretory phenotype (SASP), which may prime SnCs to inflammatory stimulation. To test this hypothesis, we examined the expression of various inflammatory cytokines and chemokines at the levels of gene transcription and protein production in various SnCs in response to lipopolysaccharide (LPS), interleukin-1β (IL1β), and tumor necrosis factor α (TNFα) stimulation.

DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas.

Background: Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patient-derived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia.

Discovery of IAP-recruiting BCL-X PROTACs as potent degraders across multiple cancer cell lines.

Targeting BCL-X via PROTACs is a promising strategy in reducing BCL-X inhibition associated platelet toxicity. Recently, we reported potent BCL-X PROTAC degraders that recruit VHL or CRBN E3 ligase. However, low protein expression or mutation of the responsible E3 ligase has been known to result in decreased protein degradation efficiency of the corresponding PROTACs.

Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity.

Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation.

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity.

The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs.