Publications by authors named "Pamela Nassau"

6 Publications

  • Page 1 of 1

Evaluation of a crystallographic surrogate for kallikrein 5 in the discovery of novel inhibitors for Netherton syndrome.

Acta Crystallogr F Struct Biol Commun 2019 May 26;75(Pt 5):385-391. Epub 2019 Apr 26.

INSERM UMR1163 Laboratory of Genetic Skin Diseases, Imagine Institute and Université Paris Descartes-Sorbonne Paris Cité, Paris, France.

The inhibition of kallikrein 5 (KLK5) has been identified as a potential strategy for treatment of the genetic skin disorder Netherton syndrome, in which loss-of-function mutations in the SPINK5 gene lead to down-regulation of the endogenous inhibitor LEKTI-1 and profound skin-barrier defects with severe allergic manifestations. To aid in the development of a medicine for this target, an X-ray crystallographic system was developed to facilitate fragment-guided chemistry and knowledge-based drug-discovery approaches. Here, the development of a surrogate crystallographic system in place of KLK5, which proved to be challenging to crystallize, is described. The biochemical robustness of the crystallographic surrogate and the suitability of the system for the study of small nonpeptidic fragments and lead-like molecules are demonstrated.
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http://dx.doi.org/10.1107/S2053230X19003169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497096PMC
May 2019

Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.

J Med Chem 2019 05 2;62(10):5096-5110. Epub 2019 May 2.

Flexible Discovery Unit , GlaxoSmithKline , 25-27 avenue du Québec , 91951 Les Ulis Cedex , France.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00318DOI Listing
May 2019

RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer.

Cancer Cell 2018 11;34(5):757-774.e7

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA.

Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIITNFαIFNγ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.
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http://dx.doi.org/10.1016/j.ccell.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836726PMC
November 2018

Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates.

Bioorg Med Chem Lett 2010 Oct 10;20(19):5695-700. Epub 2010 Aug 10.

Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.
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http://dx.doi.org/10.1016/j.bmcl.2010.08.022DOI Listing
October 2010

Synthesis and evaluation of novel alpha-amino cyclic boronates as inhibitors of HCV NS3 protease.

Bioorg Med Chem Lett 2010 Jun 20;20(12):3550-6. Epub 2010 May 20.

Anacor Pharmaceuticals, Inc., Palo Alto, CA 94303, USA.

We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.129DOI Listing
June 2010
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