A5034252974- Cancer-related Molecular Pathways
- Cancer therapeutics and mechanisms
- Protein Kinase Regulation and GTPase Signaling
- DNA Repair Mechanisms
- Chemical Synthesis and Analysis
- Chronic Lymphocytic Leukemia Research
- Biochemical and Molecular Research
- Click Chemistry and Applications
- Synthesis and biological activity
- Receptor Mechanisms and Signaling
- Advanced Breast Cancer Therapies
- Neuropeptides and Animal Physiology
- Enzyme Structure and Function
- Biomedical Research and Pathophysiology
- Synthesis and Characterization of Heterocyclic Compounds
- Cancer Mechanisms and Therapy
- Ionic liquids properties and applications
- Enzyme function and inhibition
- Quinazolinone synthesis and applications
- Advanced Synthetic Organic Chemistry
- PARP inhibition in cancer therapy
- Biochemical and Structural Characterization
- Adenosine and Purinergic Signaling
- Electrochemical Analysis and Applications
- Metabolism and Genetic Disorders
AbbVie (United States)
2014-2024
High Throughput Biology (United States)
2014
Abbott (United States)
2007-2013
Discovery Laboratories (United States)
2013
Abbott Fund
2003-2012
Boston University
2000
Washington University in St. Louis
1998-2000
Eastern Illinois University
1993
The majority of cancer therapeutics induces DNA damage to kill cells. Normal proliferating cells undergo cell cycle arrest in response damage, thus allowing repair protect the genome. induced depends on an evolutionarily conserved signal transduction network which Chk1 kinase plays a critical role. In mammalian cells, p53 and RB pathways further augment prevent catastrophic death. Given fact that most tumor suffer defects pathways, it is likely would depend more maintain than normal...
Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable sensitizing cytotoxic treatments or acting stand-alone to combat cancer. As one the strategies expand our portfolio inhibitors, we unsaturated heterocycles replace saturated cyclic amine derivatives appended benzimidazole core. Not only did a variety these new generation compounds maintain high enzymatic potency, many them also displayed robust cellular activity. For...
MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance enabling resistance to anti-tumorigenic agents including BCL-2 selective inhibitor venetoclax. The expression maintained via P-TEFb-mediated transcription, where kinase CDK9 a critical component. Consequently, we developed series potent small-molecule inhibitors CDK9, exemplified by orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules have...
A lactam-based peptidomimetic for the Phe7-Phe8 region of substance P has been synthesized. The synthesis used an anodic amide oxidation to selectively functionalize C5-position a 3-phenylproline derivative. resulting proline derivative was coupled Cbz-protected phenylalanine, and intramolecular reductive amination strategy convert material into bicyclic piperazinone ring skeleton. net result dipeptide building block that imbedded one two proposed receptor bound conformations then converted...
To investigate the role played by unique pre-DFG residue Val 195 of Cdc7 kinase on potency azaindole-chloropyridines (1), a series novel analogues with various chloro replacements were synthesized and evaluated for their inhibitory activity against Cdc7. X-ray cocrystallization using surrogate protein, GSK3β, modeling studies confirmed azaindole motif as hinge binder. Weaker hydrophobic interactions Met 134 certain (e.g., H, methyl) led to reduced inhibition. Meanwhile, data from other F, O)...
A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial The decreased interaction between the aryl groups Ser 48 in GGTase-I binding site could be one possible reason to explain improved selectivity for this new FTase inhibitors. Medicinal chemistry efforts led...
Aided by molecular modeling, compounds with a pyrimidine-based tricyclic scaffold were designed and confirmed to inhibit Wee1 kinase. Structure-activity studies identified key pharmacophores at the aminoaryl halo-benzene regions responsible for binding affinity sub-nM K i values. The potent inhibitors demonstrated sub-μM activities in both functional mechanism-based cellular assays also possessed desirable pharmacokinetic profiles. lead molecule, 31, showed oral efficacy potentiating...
Abstract The Werner syndrome helicase (WRN) has emerged as a promising synthetic lethal target in cancers with microsatellite instability (MSI). This discovery spurred numerous efforts developing therapeutics targeting WRN and the advancement of at least two programs into Phase I clinical trials. development acquired resistance remains significant obstacle for durable efficacy targeted therapies oncology this challenge may be particularly pronounced setting mismatch repair deficient (dMMR)...
Three substance P analogs with conformation constraints in the Phe7-Phe8 region have been prepared connection an effort to differentiate two families of potential conformations for binding its NK1 receptor. While did not bind receptor high affinity, synthesis demonstrated utility a general method constructing piperazinone based peptidomimetics.
Cyclin-dependent kinase 9 (CDK9) is a serine/threonine involved in the regulation of transcription elongation. An inhibition CDK9 downregulates number short-lived proteins responsible for tumor maintenance and survival, including antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing toxicity challenges clinical setting, we generated selective that could be amenable to an oral administration. Here, report lead optimization series azaindole-based...