Potent, selective, and orally bioavailable inhibitors of the mammalian target of rapamycin kinase domain exhibiting single agent antiproliferative activity. | LitMetric
Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Published: December 2012
AI Article Synopsis
Article Abstract
Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with K(i) < 10 nM for the mTOR kinase and >500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate cancer model over a 14 day study.
METTL3, an m6A methyltransferase, is integral to the regulation of messenger RNA (mRNA) biogenesis, degradation, and translation through the N6-methyladenosine (m6A) modification. Alterations in m6A homeostasis have been implicated in the development, progression, invasion, and metastasis of certain cancers. The present research aims to examine the consequences of METTL3 knockdown using short hairpin RNA (shRNA) on the proliferation and invasive capabilities of human colorectal and melanoma cancer cell lines.
Decades of basic and translational research have led to a momentum shift in dissecting the relationship between immune cells and cancer. This culminated in the emergence of breakthrough immunotherapies that paved the way for oncologists to manage certain hard-to-treat cancers. The application of high-throughput techniques of genomics, transcriptomics, and proteomics was conclusive in making and expediting the manufacturing process of cancer vaccines.
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
Aortic dissection (AD) represents a critical condition characterised by a tear in the inner lining of the aorta, leading to the leakage of blood into the layers of the aortic wall, posing a significant risk to life. However, the pathogenesis is unclear. In this study, scRNA-seq was applied to cells derived from aortas of both AD and non-AD donors (control) to unveil the cellular landscape.
Objectives: This study aimed to evaluate the efficacy of low-dose interleukin (IL-2) treatment for bullous pemphigoid (BP) caused by anti-programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors.
Methods: Low-dose IL-2 treatment was standardized for BP. The Bullous Pemphigoid Disease Area Index (BPDAI), 5D-Itch Scale (5D-IS), and Dermatology Life Quality Index (DLQI) were recorded before and after treatment, and hexachromatic lymphocytes, regulatory T cells (Treg cells), and cytokines were measured.
Background: The effect of initial antiretroviral therapy (ART) class on cancer risk in people with HIV (PWH) remains unclear.
Setting: Cohort study of 36,322 PWH enrolled (1996-2014) in the North American AIDS Cohort Collaboration on Research and Design.
Methods: We followed individuals from ART initiation (protease inhibitor [PI]-, non-nucleoside reverse transcriptase inhibitor [NNRTI]-, or integrase strand transfer inhibitor [INSTI]-based) until incident cancer, death, loss-to-follow-up, 12/31/2014, 85 months (intention-to-treat analyses [ITT]), or 30 months (per-protocol [PP] analyses).
