A cascade screening approach for the identification of Bcr-Abl myristate pocket binders active against wild type and T315I mutant.
Bioorganic & Medicinal Chemistry Letters 26(15):3436 (2016)
The major clinical challenge in drug-resistant chronic myelogenous leukemia (CML) is currently represented by the Bcr-Abl T315I mutant, which is unresponsive to treatment with common first and second generation ATP-competitive tyrosine kinase inhibitors (TKIs). Allosteric inhibition of Bcr-Abl r...
Monitoring Conformational Changes in the Receptor Tyrosine Kinase EGFR.
ChemBioChem 17(11):990 (2016)
The receptor tyrosine kinase EGFR is regulated by complex conformational changes, and this conformational control is disturbed in certain types of cancer. Many ligands are known to bind EGFR in its active conformation, thereby preventing ATP from binding. Only a few ligands are known to stabiliz...
Hope and Disappointment: Covalent Inhibitors to Overcome Drug Resistance in Non-Small Cell Lung Cancer.
ACS Medicinal Chemistry Letters 7(1):2 (2016)
In the last five years, the detailed understanding of how to overcome T790M drug resistance in non-small cell lung cancer (NSCLC) has culminated in the development of a third-generation of covalent EGFR inhibitors with excellent clinical outcomes. However, the emergence of a newly discovered acq...
Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer.
Oncotarget 6(36):38458 (2015)
Treatment with EGFR kinase inhibitors improves progression-free survival of patients with EGFR-mutant lung cancer. However, all patients with initial response will eventually acquire resistance and die from tumor recurrence. We found that intermittent high-dose treatment with erlotinib induced a...
Neuritogenic militarinone-inspired 4-hydroxypyridones target the stress pathway kinase MAP4K4.
Angewandte Chemie. International edition in Eng... 54(42):12398 (2015)
Progressive loss and impaired restoration of neuronal activity are hallmarks of neurological diseases, and new small molecules with neurotrophic activity are in high demand. The militarinone alkaloids and structurally simplified analogues with 4-hydroxy-2-pyridone core structure induce pronounce...
Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach.
Journal of medicinal and pharmaceutical chemistry 58(17):6844 (2015)
Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong ...
A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer
Cell 162(5):1169 (2015)
Covalent-Allosteric Kinase Inhibitors.
Angewandte Chemie. International edition in Eng... 54(35):10313 (2015)
Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation-dependent signaling of protein kinases. Herein the structure-based design, synthesis, and evaluation of pleckstrin homology (PH) domain-dependent covalent-allosteric inhibitors (CAIs) ...
A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer.
Cell 162(1):146 (2015)
KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell...
Structure-based design and synthesis of covalent-reversible inhibitors to overcome drug resistance in EGFR.
Bioorganic & Medicinal Chemistry 23(12):2767 (2015)
The clinical success of covalent kinase inhibitors in the treatment of EGFR-dependent non-small cell lung cancer (NSCLC) has rejuvenated the appreciation of reactive small molecules. Acquired drug resistance against first-line EGFR inhibitors remains the major bottleneck in NSCLC and is currentl...
Monitoring ligand-induced conformational changes for the identification of estrogen receptor agonists and antagonists.
Angewandte Chemie. International edition in Eng... 54(14):4379 (2015)
Nuclear receptors are transcription factors that are important targets for current drug discovery efforts as they play a role in many pathological processes. Their activity can be regulated by small molecules like hormones and drugs that can have agonistic or antagonistic functions. These ligand...
Special issue focused on two areas pertinent to chemical biology: post-translational modifications and new frontiers on kinases.
ACS Chemical Biology 10(1):1 (2015)
Discovery of inter-domain stabilizers-a novel assay system for allosteric akt inhibitors.
ACS Chemical Biology 10(1):279 (2015)
In addition to the catalytically active kinase domain, most kinases feature regulatory domains that govern their activity. Modulating and interfering with these interdomain interactions presents a major opportunity for understanding biological systems and developing novel therapeutics. Therefore...
Identification and further development of potent TBK1 inhibitors.
ACS Chemical Biology 10(1):289 (2015)
The cytosolic Ser/Thr kinase TBK1 was discovered to be an essential element in the mediation of signals that lead to tumor migration and progression. These findings meet the need for the identification of novel tool compounds and potential therapeutics to gain deeper insights into TBK1 related s...
Combining X-ray crystallography and molecular modeling toward the optimization of pyrazolo[3,4-d]pyrimidines as potent c-Src inhibitors active in vivo against neuroblastoma.
Journal of medicinal and pharmaceutical chemistry 58(1):347 (2015)
c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl i...
Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues.
Biological Chemistry 395(7-8):891 (2014)
A high-resolution crystallographic structure determination of a protein-ligand complex is generally accepted as the 'gold standard' for structure-based drug design, yet the relationship between structure and affinity is neither obvious nor straightforward. Here we analyze the interactions of a s...
Identification of type II and III DDR2 inhibitors.
Journal of medicinal and pharmaceutical chemistry 57(10):4252 (2014)
Discoidin domain-containing receptors (DDRs) exhibit a unique mechanism of action among the receptor tyrosine kinases (RTKs) because their catalytic activity is induced by extracellular collagen binding. Moreover, they are essential components in the assimilation of extracellular signals. Recent...
A special thematic compilation/special issue crossover with Biochemistry, Journal of Medicinal Chemistry, and ACS Medicinal Chemistry Letters focused on kinases.
ACS Chemical Biology 9(3):579 (2014)
Cell-autonomous and non-cell-autonomous mechanisms of transformation by amplified FGFR1 in lung cancer.
Cancer Discovery 4(2):246 (2014)
The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplified tumors are also sensitive to fibroblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other re...
FLiK: a direct-binding assay for the identification and kinetic characterization of stabilizers of inactive kinase conformations.
Methods in Enzymology 548:147 (2014)
Despite the hundreds of kinase inhibitors currently in discovery and preclinical phases, the number of FDA-approved kinase inhibitors remains very low by comparison, a discrepancy which reflects the challenges which accompanies kinase inhibitor development. Targeting protein kinases with ATP-com...