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...
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...
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...
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...
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...
Metabolically stable dibenzo[b,e]oxepin-11(6H)-ones as highly selective p38 MAP kinase inhibitors: optimizing anti-cytokine activity in human whole blood.
Journal of medicinal and pharmaceutical chemistry 56(21):8561 (2013)
Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H)-ones were synthesized and tested in a p38α enzyme assay for their inhibition of tumor necrosis factor-α (TNF-α) release in human whole blood. Compared to the monosubstituted dibenzo[b,e]oxepin-11(6H)-one derivatives, it ...
Targeting gain of function and resistance mutations in Abl and KIT by hybrid compound design.
Journal of medicinal and pharmaceutical chemistry 56(14):5757 (2013)
Mutations in the catalytic domain at the gatekeeper position represent the most prominent drug-resistant variants of kinases and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the desi...
De novo design of protein kinase inhibitors by in silico identification of hinge region-binding fragments.
ACS Chemical Biology 8(5):1044 (2013)
Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discove...
A framework for identification of actionable cancer genome dependencies in small cell lung cancer.
PNAS 109(42):17034 (2012)
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic ...
Targeting GSK3 from Ustilago maydis: type-II kinase inhibitors as potential antifungals.
ACS Chemical Biology 7(7):1257 (2012)
Protein kinases are key enzymes in the complex regulation of cellular processes in almost all living organisms. For this reason, protein kinases represent attractive targets to stop the growth of eukaryotic pathogens such as protozoa and fungi. However, using kinase inhibitors to fight against t...
A chemical genetic approach for covalent inhibition of analogue-sensitive aurora kinase.
ACS Chemical Biology 7(4):723 (2012)
The perturbation of protein kinases with small organic molecules is a powerful approach to dissect kinase function in complex biological systems. Covalent kinase inhibitors that target thiols in the ATP binding pocket of the kinase domain proved to be ideal reagents for the investigation of high...
Proteus in the world of proteins: conformational changes in protein kinases.
Archiv der Pharmazie (Weinheim) 343(4):193 (2010)
The 512 protein kinases encoded by the human genome are a prime example of nature's ability to create diversity by introducing variations to a highly conserved theme. The activity of each kinase domain is controlled by layers of regulatory mechanisms involving different combinations of post-tran...