Allosteric regulation of the tyrosine phosphatase PTP1B by a protein-protein interaction.

The rapid identification of protein-protein interactions has been significantly enabled by mass spectrometry (MS) proteomics-based methods, including affinity purification-MS, crosslinking-MS, and proximity-labeling proteomics. While these methods can reveal networks of interacting proteins, they cannot reveal how specific protein-protein interactions alter protein function or cell signaling. For instance, when two proteins interact, there can be emergent signaling processes driven purely by the individual activities of those proteins being co-localized.

Belzutifan Efficacy and Tolerability in Patients with Sporadic Metastatic Clear Cell Renal Cell Carcinoma.

Background And Objective: Belzutifan, a hypoxia-inducible factor 2 alpha inhibitor, was approved initially for patients with von Hippel-Lindau disease and more recently for sporadic, metastatic clear cell renal cell carcinoma (ccRCC) based on the results of LITESPARK-005. There is a paucity of data regarding real-world experience with belzutifan in patients with sporadic, metastatic ccRCC. This study aims to describe clinical outcomes with belzutifan in patients with sporadic, metastatic ccRCC.

Allosteric regulation of the tyrosine phosphatase PTP1B by a protein-protein interaction.

The rapid identification of protein-protein interactions has been significantly enabled by mass spectrometry (MS) proteomics-based methods, including affinity purification-MS, crosslinking-MS, and proximity-labeling proteomics. While these methods can reveal networks of interacting proteins, they cannot reveal how specific protein-protein interactions alter protein function or cell signaling. For instance, when two proteins interact, there can be emergent signaling processes driven purely by the individual activities of those proteins being co-localized.

Germ Cell Tumor of the Testis: Lethal Subtypes of a Curable Cancer.

Germ cell tumor of the testis (GCT) is a curable cancer even when it is widely metastatic; however, outcomes can differ based on tumor histology. Chemo-resistance in certain phenotypes, such as teratoma and yolk sac tumor, contributes to poor clinical outcomes in some patients with GCT. Despite this resistance to S-YSTemic therapy, many of these tumor subtypes remain amenable to surgical resection and possible cure.

Efficacy, Safety, and Tolerability of Tivozanib in Heavily Pretreated Patients With Advanced Clear Cell Renal Cell Carcinoma.

Background: Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC).

Methods: We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.

Photocatalytic Activation of Aryl(trifluoromethyl) Diazos to Carbenes for High-Resolution Protein Labeling with Red Light.

State-of-the-art methods in photoproximity labeling center on the targeted generation and capture of short-lived reactive intermediates to provide a snapshot of local protein environments. Diazirines are the current gold standard for high-resolution proximity labeling, generating short-lived aryl(trifluoromethyl) carbenes. Here, we present a method to access aryl(trifluoromethyl) carbenes from a stable diazo source tissue-penetrable, deep red to near-infrared light (600-800 nm).

Red-Light Activation of a Microtubule Polymerization Inhibitor via Amide Functionalization of the Ruthenium Photocage.

Photoactivated chemotherapy (PACT) is a promising cancer treatment modality that kills cancer cells via photochemical uncaging of a cytotoxic drug. Most ruthenium-based photocages used for PACT are activated with blue or green light, which penetrates sub-optimally into tumor tissues. Here, we report amide functionalization as a tool to fine-tune the toxicity and excited states of a terpyridine-based ruthenium photocage.

Discovery of 5-sulfonyltetrazoles as neuroblastoma differentiation agents.

Previously, we developed an innovative high-content screening (HCS) approach to quantify neuroblastoma cell differentiation based on neurite outgrowth, a morphological differentiation marker of neuroblastoma cells. Here, we report the utilization of this platform to identify 1-methyl-5-(ethylsulfonyl)-1H-tetrazole (3a) as a new neuroblastoma differentiation agent using the ChemBridge Diverset commercial synthetic small molecule compound library. We show that this activity can be extended to a group of analogues, which can be accessed via a short two-step synthetic sequence.

Risk Factors for Immune Checkpoint Inhibitor Immunotherapy Toxicity Among Older Adults with Cancer.

Objectives: Immune checkpoint inhibitor immunotherapy (IO) is revolutionizing cancer care but can lead to significant toxicity. This study seeks to describe potential risk factors for immune-related adverse events (irAEs) specifically among older adults.

Materials And Methods: This was a retrospective study at a single academic comprehensive cancer center based on chart review data abstracted by physicians.

Mapping the Chemical Space of Active-Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases.

Protein tyrosine phosphatases (PTPs) are an important class of enzymes that modulate essential cellular processes through protein dephosphorylation and are dysregulated in various disease states. There is demand for new compounds that target the active sites of these enzymes, for use as chemical tools to dissect their biological roles or as leads for the development of new therapeutics. In this study, we explore an array of electrophiles and fragment scaffolds to investigate the required chemical parameters for covalent inhibition of tyrosine phosphatases.

Association of medical comorbidities and cardiovascular disease with toxicity and survival among patients receiving checkpoint inhibitor immunotherapy.

Background And Objectives: Medical comorbidities (MC) are highly prevalent among patients with cancer and predict worse outcomes for traditional therapies. This association is poorly understood for checkpoint inhibitor immunotherapy (IO). We aimed to explore the relationship between common MC including cardiovascular disease (CVD), immune-related adverse events (irAEs), and overall survival (OS) among patients receiving IO for advanced cancer.

Toxicities From Antibody-Drug Conjugates.

Antibody-drug conjugates are becoming increasingly important in the treatment of many cancer types. The 3 main structural components-antibody, linker, and payload-each contribute to the toxicity profiles of these drugs. In addition to cytopenias and gastrointestinal adverse effects attributed to the chemotherapy payloads, each drug has specific toxicities that are not commonly described in oncology.

Checkpoint inhibitor immunotherapy toxicity and overall survival among older adults with advanced cancer.

Objectives: Despite growing evidence that checkpoint inhibitor immunotherapy (IO) toxicity is associated with improved treatment response, the relationship between immune-related adverse events (irAEs) and overall survival (OS) among older adults [age ≥ 70 years (y)] remains unknown. The study goal was to determine differences in OS based on age and ≥ grade 3 (G3) irAEs.

Materials And Methods: This was a retrospective cohort study of 673 patients with advanced cancer.