A5070605323- Synthetic Organic Chemistry Methods
- Cell death mechanisms and regulation
- Chemical Synthesis and Analysis
- Asymmetric Synthesis and Catalysis
- Cancer-related Molecular Pathways
- Asymmetric Hydrogenation and Catalysis
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- Cancer Mechanisms and Therapy
- Nanoparticle-Based Drug Delivery
- ATP Synthase and ATPases Research
- Computational Drug Discovery Methods
- Cancer therapeutics and mechanisms
- Monoclonal and Polyclonal Antibodies Research
- RNA Interference and Gene Delivery
- Chronic Lymphocytic Leukemia Research
- Advanced Breast Cancer Therapies
- Hedgehog Signaling Pathway Studies
- Phagocytosis and Immune Regulation
- Microtubule and mitosis dynamics
- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Advanced Synthetic Organic Chemistry
AstraZeneca (United States)
2012-2023
University of Manchester
2021
AstraZeneca (United Kingdom)
2012-2017
Boston College
2003-2006
Abstract Mcl-1 is a member of the Bcl-2 family proteins that promotes cell survival by preventing induction apoptosis in many cancers. High expression causes tumorigenesis and resistance to anticancer therapies highlighting potential inhibitors as drugs. Here, we describe AZD5991, rationally designed macrocyclic molecule with high selectivity affinity for currently clinical development. Our studies demonstrate AZD5991 binds directly induces rapid cancer cells, most notably myeloma acute...
We present the first examples of Cu-catalyzed enantioselective conjugate additions alkyl- and arylzinc reagents to unactivated cyclic β-substituted enones. Transformations are promoted in presence 2.5−15 mol % a readily available chiral NHC-based Cu complex, affording desired products bearing all-carbon quaternary stereogenic centers 67→98% yield up 97% ee. Catalytic reactions can be carried out on benchtop, with undistilled solvent commercially (not further purified) salts. Mechanistic...
A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis cancer cells dependent on for survival. We report the optimization series amidopyridines (from compound 2), focusing properties suitable achieving after intravenous administration. By increasing potency and human metabolic clearance, we identified 24, potent selective with predicted pharmacokinetic to deliver transient inhibition CDK9. Furthermore, solubility 24 was considered...
Amino acid-based chiral ligands have been developed for use in Cu-catalyzed enantioselective allylic alkylations and conjugate additions that allow access to optically enriched compounds are otherwise difficult prepare. These easily modified identified through mechanism-based library screening. The data presented point the significance of availability a collection catalysts, since subtle variations substrate or nucleophile structure often call different optimal ligand. Can catalyst be truly...
A method for Cu-catalyzed asymmetric conjugate addition (ACA) of dialkylzinc reagents to tetrasubstituted five- and six-membered cyclic enones that afford quaternary all-carbon stereogenic centers in up 95% ee is reported. Catalytic ACAs are practical efficient. Reactions proceed >98% conversion undistilled commercial grade toluene the presence 2 mol % an air-stable Cu salt (CuCN) a readily available chiral ligand. Enantioselective ACA reactions deliver products can be functionalized variety...
A series of dimeric compounds based on the AVPI motif Smac were designed and prepared as antagonists inhibitor apoptosis proteins (IAPs). Optimization cellular potency, physical properties, pharmacokinetic parameters led to identification compound 14 (AZD5582), which binds potently BIR3 domains cIAP1, cIAP2, XIAP (IC50 = 15, 21, 15 nM, respectively). This causes cIAP1 degradation induces in MDA-MB-231 breast cancer cell line at subnanomolar concentrations vitro. When administered...
A chiral triamide phosphane promotes highly efficient and enantioselective Cu-catalyzed conjugate additions of alkyl zinc compounds to unsaturated oxazolidinones (see scheme). The resulting β-alkyl are readily converted into synthetically useful carbonyl not accessible by alternative catalytic methods. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2003/z50699_s.pdf or from author. Please note: publisher responsible content...
Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of often seen in various tumors allows cancer cells evade apoptosis. Here we report the discovery optimization series non-natural peptide inhibitors. Screening DNA-encoded libraries resulted hit compound 1, 1.5 μM inhibitor. A subsequent crystal structure demonstrated that 1 bound β-turn conformation, such two ends were close together. This proximity allowed for linking form macrocycle....
The three-dimensional conformations adopted by a free ligand in solution impact bioactivity and physicochemical properties. Solution 1D NMR spectra inherently contain information on conformational flexibility shape, as well the propensity of to fully preorganize into bioactive conformation. Herein we discuss some key learnings, distilled from our experience developing potent selective synthetic macrocyclic inhibitors, including Mcl-1 clinical candidate AZD5991. Case studies have been...
Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 from different chemical scaffolds have been developed and evaluated in clinical trials combination with chemotherapeutics radiation treatment. Scaffold morphing thiophene carboxamide ureas (TCUs), such as AZD7762 (1) a related series triazoloquinolines (TZQs), led to identification fused-ring bicyclic inhibitors,...
Optimization of a series azabenzimidazoles identified from screening hit 2 and the information gained co-crystal structure azabenzimidazole-based lead 6 bound to CDK9 led discovery azaindoles as highly potent selective inhibitors. With goal discovering inhibitor administrated intravenously that would enable transient target engagement for treatment hematological malignancies, further optimization focusing on physicochemical pharmacokinetic properties 38 39. These compounds are inhibitors...
When activated by amino acid starvation, the stress sensing protein kinase GCN2 phosphorylates eukaryotic initiation factor 2 alpha, inhibiting translation to conserve energy and facilitate cell survival. Amino particularly of tryptophan arginine, affects immune tolerance suppressing differentiation proliferation T-cells via activation kinase. In addition, pathway mediates cancer survival directly within context metabolic stress. Here, we report first crystal structures human domain (KD) in...
Abstract Mcl-1, a member of the Bcl/Mcl family, is key protein involved in evasion apoptosis wide variety tumors. Its amplification and overexpression have also been implicated innate acquired resistance to anticancer drugs. Mcl-1 capable preventing induction apoptosis, both by binding inactivating pro-apoptotic executioner Bcl-2 protein, Bak, as well sequestering other BH3-only proteins such Bim Noxa. AZD5991 rationally designed macrocycle with sub-nanomolar affinity for Mcl-1. It...
Ein chirales Triamidophosphan vermittelt die hoch effiziente und enantioselektive Cu-katalysierte konjugate Addition von Zinkalkylen an ungesättigte Oxazolidinone (siehe Schema). Die entstehenden chiralen β-Alkyloxazolidinone werden leicht in synthetisch wertvolle Carbonylverbindungen überführt, durch alternative katalytische Methoden nicht zugänglich sind. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2003/z50699_s.pdf or from...
The structure-based design of small-molecule inhibitors targeting protein-protein interactions (PPIs) remains a huge challenge as the drug must bind typically wide and shallow protein sites. A PPI target high interest for hematological cancer therapy is myeloid cell leukemia 1 (Mcl-1), prosurvival guardian from Bcl-2 family. Despite being previously considered undruggable, seven Mcl-1 have recently entered clinical trials. Here, we report crystal structure clinical-stage inhibitor AMG-176...
Abstract Cyclin-dependent kinase 9 (CDK9) is a serine/threonine that regulates elongation of transcription through phosphorylation RNA polymerase II at serine 2 (p-Ser2-RNAPII). Transient inhibition CDK9 results in reduced protein levels for genes have short half-lives transcripts and proteins, thus presenting potential therapeutic opportunity tumors dependent upon oncogenes fitting such criteria. One example Mcl-1, an anti-apoptotic plays key role cancer cell survival. A potent selective...