Showing papers by "Incyte published in 2022"
TL;DR: Capparelli et al. as discussed by the authors proposed a small-molecule inhibitor of PD-L1 called INCB086550, which has biological properties similar to PDL1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy.
Abstract: Abstract Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34+ humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies. Significance: We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach. See related commentary by Capparelli and Aplin, p. 1413. This article is highlighted in the In This Issue feature, p. 1397
22 citations
TL;DR: In this article , the need for an operationally straightforward application of radical chemistry has led researchers to explore practical strategies to obtain and trap radicals, which has led to the development of a number of applications in the field.
5 citations
TL;DR: A broad proteomic analysis was conducted to identify and evaluate candidate biomarkers potentially predictive of response to treatment with an oral selective Janus kinase 1 (JAK1) inhibitor, itacitinib, in acute graft-versus-host disease (GVHD) as discussed by the authors .
Abstract: A broad proteomic analysis was conducted to identify and evaluate candidate biomarkers potentially predictive of response to treatment with an oral selective Janus kinase 1 (JAK1) inhibitor, itacitinib, in acute graft-versus-host disease (GVHD). Plasma samples from 25 participants (identification cohort; NCT02614612) were used to identify novel biomarkers that were tested in a validation cohort from a placebo-controlled, randomised trial (n = 210; NCT03139604). The identification cohort received corticosteroids plus 200 or 300 mg itacitinib once daily. The validation cohort received corticosteroids plus 200 mg itacitinib once daily or placebo. A broad proteomic analysis was conducted using a proximity extension assay. Baseline and longitudinal comparisons were performed with unpaired t-test and one-way analysis of variance used to evaluate biomarker level changes. Seven candidate biomarkers were identified. Monocyte-chemotactic protein (MCP)3, pro-calcitonin/calcitonin (ProCALCA/CALCA), together with a previously identified prognostic acute GVHD biomarker, regenerating islet-derived protein (REG)3A, stratified complete responders from non-responders (participants with progressive disease) to itacitinib, but not placebo, potentially representing predictive biomarkers of itacitinib in acute GVHD. ProCALCA/CALCA, suppressor of tumorigenicity (ST)2, and tumour necrosis factor receptor (TNFR)1 were significantly reduced over time by itacitinib in responders, potentially representing response-to-treatment biomarkers. Novel biomarkers have the potential to identify patients with acute GVHD that may respond to itacitinib plus corticosteroid treatment (NCT02614612; NCT03139604).
3 citations
TL;DR: In this paper, a bicyclic lactam series of potent and selective ALK2 inhibitors was proposed, achieving an improvement in potency of two orders of magnitude from the initial bicyclic structure as well as a two-fold improvement in cellular potency from the original monocyclic inhibitor.
2 citations
13 Sep 2022
TL;DR: In this article , the frequency of new particle formation (NPF) events exhibited extreme distinction with 15 % in pre-monsoon season and 80 % in monsoon season, while condensation sink and gaseous sulfuric acid had no effect.
Abstract: Abstract. New particle formation (NPF) is an important source of cloud condensation nuclei (CCN), which affects Earth’s radiative balance and global climate. The mechanism and CCN contribution of NPF at the high-altitude mountains, especially in the Tibetan Plateau (TP), was unclear due to lack of measurements. In this study, intensive measurements were conducted at Nam Co station (4379 m a.s.l) in the central TP during both pre-monsoon and summer monsoon seasons. The frequencies of NPF events exhibited extreme distinction with 15 % in pre-monsoon season and 80 % in monsoon season. The level of organic vapours governed the occurrence of NPF events, while condensation sink and gaseous sulfuric acid had no effect. The frequent NPF events in summer monsoon season resulted from the higher concentration of organic vapours, which was brought from northeast India by the strong southerly monsoon. It had increased the aerosol number concentrations and CCN at supersaturation of 1.2 % by more than 2 and 0.5 times compared with those in pre-monsoon season, respectively. Considering that the smaller particles formed by NPF may further grow and reach CCN size during the following days due to the low-level coagulation sink, the amount of potential CCN in monsoon season could be much larger than our local measurement results. Our results emphasized the importance of organics to NPF in high-altitude atmosphere, and the seasonal effect of NPF at the high-altitude sites should be carefully considered in model simulations to reduce the uncertainty of global CCN budget.