The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ (PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγ offers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγ inhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγ inhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγ inhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667872PMC
http://dx.doi.org/10.1021/acsmedchemlett.0c00387DOI Listing

Publication Analysis

Top Keywords

pi3kγ inhibitors
12
pi3kγ
6
discovery potent
4
potent selective
4
selective 7-azaindole
4
7-azaindole isoindolinone-based
4
isoindolinone-based pi3kγ
4
inhibitors
4
inhibitors successful
4
successful application
4

Similar Publications

Objective: To determine the association between concurrent statin use with immune checkpoint inhibitors (ICIs) and lung cancer-specific and overall mortality in patients with nonsmall cell lung cancer (NSCLC).

Materials And Methods: SEER-Medicare was used to conduct a retrospective study of Medicare beneficiaries ≥65 years of age diagnosed with NSCLC between 2007 and 2017 treated with an ICI. Patients were followed from date of first ICI claim until death, 1 month from last ICI claim, or 12/31/2018, whichever came first.

View Article and Find Full Text PDF

Background: The efficacy of trifluridine/tipiracil (FTD/TPI) + bevacizumab compared to FTD/TPI for treatment of refractory metastatic colorectal cancer (mCRC) was demonstrated in the SUNLIGHT trial. This analysis of SUNLIGHT investigated the impact of treatment with FTD/TPI + bevacizumab on patient quality of life (QoL) and Eastern Cooperative Oncology Group performance status (ECOG PS).

Methods: Questionnaires (EORTC QLQ-C30 and EQ-5D-5L) and ECOG PS assessments were conducted at baseline and on Day 1 of each treatment cycle.

View Article and Find Full Text PDF

Tyrosine Kinase Inhibitor Treatment Patterns in Patients With Chronic-Phase Chronic Myeloid Leukemia: A Single Center Data From China.

Clin Lymphoma Myeloma Leuk

December 2024

Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Hematology Center, Peking University People's Hospital, Qingdao, China. Electronic address:

Aim: To describe tyrosine kinase inhibitor (TKI) treatment patterns and analyze co-variates of TKI switch for chronic myeloid leukemia (CML) patients in a center from China.

Methods: A retrospectively study was designed to analyze TKI switching patterns, reasons and associated covariates in patients with CP-CML.

Results: 1766 patients receiving initial imatinib (n = 1374), nilotinib (n = 254), dasatinib (n = 63) and flumatinib (n = 75) therapy were retrospectively interrogated.

View Article and Find Full Text PDF

Unfolded protein response modulates Tyrosinase levels and melanin production during melanogenesis.

J Dermatol Sci

January 2025

Department of Biochemistry, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Department of Frontier Science and Interdisciplinary Research, Faculty of Medicine, Kanazawa University, Ishikawa, Japan. Electronic address:

Background: Melanocytes protect the body from ultraviolet radiation by synthesizing melanin. Tyrosinase, a key enzyme in melanin production, accumulates in the endoplasmic reticulum (ER) during melanin synthesis, potentially causing ER stress. However, regulating ER function for melanin synthesis has been less studied than controlling Tyrosinase activity.

View Article and Find Full Text PDF

Environmental and Clinical Factors Concerning Gastrointestinal Bleeding: An Umbrella Review of Meta-Analyses.

J Am Med Dir Assoc

January 2025

Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University/Second Faculty of Clinical Medicine, Kunming Medical University, Kunming, China.

Objectives: Gastrointestinal bleeding, an emergency and critical disease, is affected by multiple factors. This study aims to systematically summarize and appraise various factors associated with gastrointestinal bleeding.

Design: Umbrella review.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!