A5066313823- Cytokine Signaling Pathways and Interactions
- Chemical Synthesis and Analysis
- Mathematical Biology Tumor Growth
- Lung Cancer Treatments and Mutations
- Photochromic and Fluorescence Chemistry
- Estrogen and related hormone effects
- Cancer therapeutics and mechanisms
- HER2/EGFR in Cancer Research
- Radiopharmaceutical Chemistry and Applications
- Protein Degradation and Inhibitors
- Chronic Myeloid Leukemia Treatments
- Synthesis and Reactions of Organic Compounds
- Monoclonal and Polyclonal Antibodies Research
- Receptor Mechanisms and Signaling
- Quinazolinone synthesis and applications
- Phenothiazines and Benzothiazines Synthesis and Activities
- DNA Repair Mechanisms
- Computational Drug Discovery Methods
- Synthesis and Biological Evaluation
- Synthesis and biological activity
- Angiogenesis and VEGF in Cancer
- PARP inhibition in cancer therapy
- Cancer Treatment and Pharmacology
- Adenosine and Purinergic Signaling
- Analytical Chemistry and Chromatography
Dana-Farber Cancer Institute
2017-2024
AstraZeneca (United States)
2005-2023
Harvard University
2017-2022
University of Richmond
1989-1990
Tulane University
1984
Allosteric kinase inhibitors offer a potentially complementary therapeutic strategy to ATP-competitive due their distinct sites of target binding. In this study, we identify and study mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as single agent can inhibit cell proliferation EGFRL858R/T790M/C797S signaling in vitro vivo. However, increased dimer formation limits treatment efficacy leads drug resistance. Remarkably, osimertinib, an covalent uniquely significantly enhances...
Allosteric kinase inhibitors represent a promising new therapeutic strategy for targeting kinases harboring oncogenic driver mutations in cancers. Here, we report the discovery, optimization, and structural characterization of allosteric mutant-selective EGFR comprising 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one scaffold. Our structure-based medicinal chemistry effort yielded an inhibitor (3) EGFR(L858R/T790M) EGFR(L858R/T790M/C797S) mutants with IC50 ∼10 nM high selectivity, as...
Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results cell cycle arrest, allowing sufficient time for repair. Agents lead abrogation of such checkpoints have potential increase the efficacy compounds as chemo- radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified inhibitors by high throughput screening. A structure-based approach is described using crystal structures JNK1 complex with 1 2 CHK1-3b complex. The ribose binding pocket was targeted...
Abstract Purpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, had success the clinic, another member, Bcl-xL, also target and mechanism resistance. Therefore, we developed dual Bcl-2/Bcl-xL inhibitor that broadens therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design small-molecule Bcl-xL...
A series of novel benzo- and pyrido-1,4-oxazepinones -thiones which represents a new structural class compounds possessing H1 antihistaminic activity was synthesized, the SARs were evaluated. The determined by blockade histamine-induced lethality in guinea pigs. sedative potential comparison EEG profiles with those known sedating nonsedating antihistamines. Several shown to possess potent be free cortical slowing synchronized waves spindling found One compound,...
Abstract Medulloblastoma is one of the most common malignant brain tumors children, and 30% medulloblastomas are driven by gain-of-function genetic lesions in Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase transcription factor, critical for tumorigenesis proliferation SHH medulloblastoma (SHH-MB). Benzarone benzbromarone have been identified as allosteric inhibitors EYA proteins. Using benzarone point departure, we developed panel 35 derivatives tested them...
Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and thus implicated both cancer inflammatory diseases. The JAK family consists of four highly homologous members: JAK1–3 TYK2. development small-molecule inhibitors that are selective for a specific member would represent desirable tools deconvoluting the intricacies biology. Herein, we report discovery potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over other members (determined by biochemical...
The enantiomers of 2-[2-(dimethylamino)ethyl]-3,4-dihydro-4-methylpyrido[3,2-f]-1,4- oxazapine-5(2H)-thione (rocastine) and two its more potent analogues were prepared with an enantiomeric purity greater than 99.9%. antihistaminic activity these compounds was assessed by their ability to block histamine-induced lethality in guinea pigs inhibit [3H]mepyramine binding pig cortex. In this series, having the R configuration at 2-position are least 300 times S isomers. Conformational analysis...
Abstract An improved method for the preparation of primary carboxylic acid amides from corresponding esters is described. This reaction was easily followed by GLC and usually complete in less than one hour.
Abstract While osimertinib is highly efficacious in lung cancers with sensitizing mutations EGFR, there a major unmet need for agents that overcome resistance to it and other covalent third-generation EGFR TKIs due the C797S mutation. Furthermore, extends overall survival patients exon19 deletions but offers little improvement L858R mutation relative first-generation inhibitors. We are developing EAI-432 goal of improving outcomes EGFRL858R+ cancer. mutant-selective allosteric inhibitor...
Abstract A convenient method to prepare 5-halo-2-hydroxy-nicotinic acid is described.