A5015725755- Synthetic Organic Chemistry Methods
- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Heat shock proteins research
- Biochemical and Molecular Research
- Cancer-related Molecular Pathways
- Hedgehog Signaling Pathway Studies
- Epigenetics and DNA Methylation
- Oxidative Organic Chemistry Reactions
- Toxin Mechanisms and Immunotoxins
- Marine Sponges and Natural Products
- Click Chemistry and Applications
- Chronic Lymphocytic Leukemia Research
- Oral and gingival health research
- Crystallization and Solubility Studies
- Chemical synthesis and alkaloids
- Enzyme Structure and Function
- Computational Drug Discovery Methods
- Veterinary medicine and infectious diseases
- Ubiquitin and proteasome pathways
- Microbial Natural Products and Biosynthesis
- PI3K/AKT/mTOR signaling in cancer
- X-ray Diffraction in Crystallography
- Connective tissue disorders research
- Microtubule and mitosis dynamics
Biogen (United States)
2016-2023
Amgen (United States)
2010-2022
NKT Therapeutics (United States)
2022
University of Wisconsin–Madison
2003-2007
Memorial Sloan Kettering Cancer Center
2001-2004
B.C. Women's Hospital & Health Centre
1999
University of British Columbia
1999
Abstract The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of protein–protein interactions, we rigorously applied small-molecule conformational restriction, which culminated discovery AMG 176, first selective inhibitor to be studied humans. We demonstrate that induces a rapid and committed step toward apoptosis subsets hematologic cancer cell lines, tumor xenograft models, primary patient samples....
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor MDM2-p53 interaction. Continued research investigation N-alkyl substituent this series, focused in particular on previously underutilized interaction shallow cleft MDM2 surface, led to one-carbon tethered sulfone which gave rise substantial improvements biochemical cellular potency. Further produced AMG 232 (2), is currently being evaluated human clinical trials for treatment cancer. Compound 2...
The development and optimization of a series quinolinylpurines as potent selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification 1 (AMG319), compound an IC50 16 nM in human whole blood assay (HWB), selectivity over large panel protein kinases, high level vivo efficacy measured by two rodent disease models inflammation.
Challenge met: In the synthesis of phorboxazole B, a highly efficient hetero-Diels–Alder reaction was used to construct key C33–C39 linchpin, allowing for completion C18–C46 fragment (see picture). Coupling with suitable C3–C17 partner followed by late-stage formation oxazole unit, macrocyclization, and deprotection afford synthetic B. Supporting information this article is available on WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z603656_s.pdf or from author. Please note: The...
The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by low yield initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, highly diastereoselective allylation, and novel oxazoline-assisted piperidinone forming reaction to provide in 35.6% 11 steps.
Combining a phenotypic screen with chemoproteomics reveals CDK12 as potential therapeutic target to inhibit noncanonical NF-κB in inflammation and cancer.
Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition both paralogs, leading activation Wnt/β-catenin pathway and potential aberrant cell proliferation. Development GSK3α or GSK3β paralog-selective that could offer an improved profile reported but further advancement hampered by lack structural information GSK3α. Here...
meso-Tetraol bis(allylic acetates) 2 and 5 were synthesized via two-directional chain elongation. A palladium-mediated, ligand-controlled desymmetrization provided the desired bis-oxanes in greater than 98% ee. Bis-oxanes 1 4 represent potential synthetic intermediates for C3−C17 subunits of phorboxazoles B.
The C1−C17 bis-oxane subunit 22 of phorboxazole B is efficiently synthesized by exploiting differential reactivities between similar substituents on the hydropyran rings in 4. Selective dihydroxylation equatorial vinyl group, hydroboration axial and intramolecular Mitsunobu lactonization serve to fully differentiate hydropyrans.
An efficient synthesis of the C20−C32 segment phorboxazoles has been achieved using an enantioselective hetero Diels−Alder reaction catalyzed by Jacobsen's Cr(III) amino indanol Schiff base catalyst.
Optimization of the potency and pharmacokinetic profile 2,3,4-trisubstituted quinoline, 4, led to discovery two potent, selective, orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) 7 (AM-1430). On basis their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) efficacy experiments animal models inflammation. The PD studies, which carried out a mouse pAKT inhibition model, confirmed observed biochemical cellular assays. Efficacy keyhole limpet hemocyanin model rats...
ADVERTISEMENT RETURN TO ISSUEPREVReportNEXTFacile Synthesis of a Library 9-Alkyl-8-benzyl-9H-purin-6-ylamine DerivativesBrian Lucas, Neal Rosen, and Gabriela ChiosisView Author Information Department Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 271, New York, 10021 Cite this: J. Comb. Chem. 2001, 3, 6, 518–520Publication Date (Web):September 21, 2001Publication History Received12 April 2001Published online21 September inissue 1 November...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDevelopment of an Efficient Process for the Preparation Sch 39166: Aziridinium Chemistry on ScaleDinesh Gala, Vilas H. Dahanukar, Jeffery M. Eckert, Brian S. Lucas, Doris P. Schumacher, Ilia A. Zavialov, Patrik Buholzer, Peter Kubisch, Ingrid Mergelsberg, and Dominik SchererView Author Information Schering-Plough Research Institute, Department Synthetic Chemistry, 1011 Morris Avenue, Union, New Jersey 07083, U.S.A. Chemical Development Department,...
Ziel erreicht: Bei der Synthese von Phorboxazol B wurde mit einer hocheffizienten Hetero-Diels-Alder-Reaktion das zentrale C33-C39-Schlüsselelement erhalten, dem C18-C46-Fragment vervollständigt werden konnte (siehe Bild). Der Kupplung einem geeigneten C3-C17-Partner folgten die späte Bildung Oxazoleinheit, Makrocyclisierung und Entschützen zu synthetischem B.
Abstract A chiral Cu(II)-PyBOX complex was prepared and utilized to accomplish desymmetrization of a 1,3-diol en route AMG 176. An expedient synthesis the racemic is described, in addition efforts for rapid optimization subsequent kilogram-scale execution process generate material pre-clinical activities. overview provided.