A5063661309- Down syndrome and intellectual disability research
- 14-3-3 protein interactions
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Thermal and Kinetic Analysis
- Heat shock proteins research
- ATP Synthase and ATPases Research
- Chemical Thermodynamics and Molecular Structure
- Cell death mechanisms and regulation
- Carbohydrate Chemistry and Synthesis
- Endoplasmic Reticulum Stress and Disease
- Synthesis and Reactivity of Heterocycles
- Crystallization and Solubility Studies
- Glycosylation and Glycoproteins Research
- Nanoparticle-Based Drug Delivery
- Monoclonal and Polyclonal Antibodies Research
- Cancer therapeutics and mechanisms
- Crystallography and molecular interactions
- Plant biochemistry and biosynthesis
- Enzyme Structure and Function
- Advanced Chemical Physics Studies
- X-ray Diffraction in Crystallography
- Signaling Pathways in Disease
- Peptidase Inhibition and Analysis
- Solid-state spectroscopy and crystallography
Granta Design (United Kingdom)
2005-2023
Institute of Cancer Research
2006
The Honourable Society of Lincoln's Inn
1998-2000
Gdańsk University of Technology
2000
University of Gdańsk
1990-1999
Adam Mickiewicz University in Poznań
1991
The design and synthesis of novel adenosine-derived inhibitors HSP70, guided by modeling X-ray crystallographic structures these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for were highly selective over HSP90, some displayed potency against HCT116 cells. Exposure compound 12 to cells caused significant reduction cellular levels Raf-1 Her2 at concentrations similar that which cell growth arrest.
Escape from apoptosis is one of the major hallmarks cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators apoptotic process. Overexpression pro-survival member BCL-2 a well-established mechanism contributing to oncogenesis chemoresistance in several cancers, including lymphoma leukemia. Thus, has become an attractive target for therapeutic strategy cancer, as demonstrated by recent approval ABT-199 (Venclexta™)...
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is antiapoptotic member of the Bcl-2 family proteins, whose upregulation in human cancers associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report discovery our clinical candidate S64315, a selective small molecule inhibitor Mcl-1. Starting from fragment derived lead compound, have conducted structure guided optimization that led significant (3 log) improvement...
78 kDa glucose-regulated protein (Grp78) is a heat shock (HSP) involved in folding that plays role cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and isothermal titration calorimetry. The most potent compounds were 13 (VER-155008) with K(D) = 80 nM 14 60 nM. X-ray crystal structures bound ATP, ADPnP, adenosine derivative 10 revealed differences the binding site between homologous proteins.
Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as attractive target for cancer therapy. Here, we report discovery selective small molecule inhibitors Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids promising but nonselective hits were optimized using nuclear...
We describe our work to establish structure- and fragment-based drug discovery identify small molecules that inhibit the anti-apoptotic activity of proteins Mcl-1 Bcl-2. This identified hit series compounds, some which were subsequently optimized clinical candidates in trials for treating various cancers. Many protein constructs designed with suitable properties different biophysical assays structural methods. Fragment screening using ligand-observed NMR experiments several compounds each...
// Patrick Casara 1, * , James Davidson 2, Audrey Claperon 3, Gaëtane Le Toumelin-Braizat 3 Meike Vogler 4 Alain Bruno 5 Maïa Chanrion Gaëlle Lysiak-Auvity Thierry Diguarher 1 Jérôme-Benoît Starck Ijen Chen 2 Neil Whitehead Christopher Graham Natalia Matassova Pawel Dokurno Pedder Youzhen Wang 6 Shumei Qiu Anne-Marie Girard Emilie Schneider Fabienne Gravé Aurélie Studeny Ghislaine Guasconi Francesca Rocchetti Sophie Maïga 7 Jean-Michel...
The serine/threonine kinase DYRK1A has been implicated in regulation of a variety cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, differentiation, and metastasis. In addition, elevated-level activity increased severity symptoms Down's syndrome. A selective inhibitor could therefore be therapeutic benefit. We have used fragment structure-based discovery methods to identify highly selective, well-tolerated,...
Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 domain based on checkpoint 1 (CHK1) mutants were designed, expressed insect cells infected baculovirus, purified, and crystallized. X-ray structures surrogates complexed known inhibitors rationalized compound potency selectivity. The CHK1 10-point mutant was preferred, following assessment surrogate binding affinity inhibitors....
The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified simple biaryl compound that bound the ATP site with very high efficiency, although limited selectivity. Structure-guided optimization cycles enabled us convert this hit into potent and selective inhibitors. Exploiting structural differences close homologue DYRK2, were able fine-tune selectivity of our Our best compounds potently inhibited...
Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures LRRK2 domain surrogates, based on checkpoint 1 (CHK1) a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi 0.7 nM, LE 0.66) was identified, with increased potency consistent an structure 18/CHK1 10-pt. mutant showing the 2-methyl...
Several generations of ATP-competitive anti-cancer drugs that inhibit the activity intracellular kinase domain epidermal growth factor receptor (EGFR) have been developed over past twenty years. The first-generation such as gefitinib bind reversibly and were followed by a second-generation dacomitinib harbor an acrylamide moiety forms covalent bond with C797 in ATP binding pocket. Resistance emerges through mutation T790 gatekeeper residue to methionine, which introduces steric hindrance...
Abstract Mcl-1 is highly expressed in a variety of human cancers (including those hematopoietic and lymphoid origin) exploited by cancer cells to evade cell death develop resistance diverse chemotherapeutic agents. We disclose, for the first time, structure S64315 (also named MIK665) potent selective inhibitor with improved potency over its predecessor S63845 (Kotschy et al, Nature, 2016). S64315/MIK665 currently phase 1 AML (Acute Myeloid Leukemia) MDS (Myelodysplastic Syndrome) (EudraCT...