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Concept

Dasatinib

Publications associées (22)

Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial

Sebastian Martin Waszak

PURPOSE The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammali ...

2023

Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-ABL1(T315I) and BCR-ABL1(T315I-E255K)

Oliver Hantschel

Resistance remains the major clinical challenge for the therapy of Philadelphia chromosome-positive (Ph+) leukemia. With the exception of ponatinib, all approved tyrosine kinase inhibitors (TKIs) are unable to inhibit the common "gatekeeper" mutation T315I ...

SPRINGER2021

Phosphorylation of the overlooked tyrosine 310 regulates the structure, aggregation, and microtubule- and lipid-binding properties of Tau

Hilal Lashuel, Anass Chiki, Galina Limorenko, Nadine Aït Bouziad

The microtubule-associated protein Tau is implicated in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. Increasing evidence suggests that post-translational modifications play critical roles in regulating Tau's norma ...

2020

Rapid Screen for Tyrosine Kinase Inhibitor Resistance Mutations and Substrate Specificity

Oliver Hantschel, Sandrine Madeleine Suzanne Georgeon, Sina Maren Reckel

We present a rapid and high-throughput yeast and flow cytometry based method for predicting kinase inhibitor resistance mutations and determining kinase peptide substrate specificity. Despite the widespread success of targeted kinase inhibitors as cancer t ...

AMER CHEMICAL SOC2019

Allosteric kinase inhibitors

Oliver Hantschel

Background. Inhibition of the kinase activity of the BCR-ABL1 oncoprotein by an allosteric mechanism of action facilitates alternative treatment options for chronic myeloid leukemia (CML) patients who cannot be adequately treated with conventional catalyti ...

Springer Nature2017

Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase

Oliver Hantschel, Florence Pojer, Sandrine Madeleine Suzanne Georgeon, Sina Maren Reckel, Charlotte Julie Caroline Gehin, Tim Kükenshöner, Delphine Maude Tardivon, Barbara Gerig

The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To provide a molecular rationale for these observations, we study ...

Springer Nature2017

Allosteric regulation and targeting of Abl SH2-kinase interface and other cytoplasmic tyrosine kinases

Allan Joaquim Lamontanara

Due to their central role in normal cellular physiology, the activity of protein kinases is tightly regulated and their aberrant activation can lead to cancer. Chronic myelogenous leukemia (CML) is a blood cancer characterized by unregulated growth of myel ...

EPFL2016

Allosteric Inhibition of Bcr-Abl Kinase by High Affinity Monobody Inhibitors Directed to the Src Homology 2 (SH2)-Kinase Interface

Oliver Hantschel, Allan Joaquim Lamontanara, Barbara Gerig

Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase do ...

American Society for Biochemistry and Molecular Biology2016

Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases

Oliver Hantschel

Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examine ...

American Society of Hematology2016

Targeting BCR-ABL and JAK2 in Ph+ ALL

Oliver Hantschel

In this issue of Blood, Appelmann et al provide evidence for prolonged survival and prevention of resistance in a mouse model of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) by combined targeting of the BCR-ABL kinase and Janus ...

2015

Improved Angiostatic Activity of Dasatinib by Modulation with Hydrophobic Chains

Paul Joseph Dyson, Patrycja Nowak-Sliwinska, Catherine Marie Amélie Clavel, Emilia Paunescu

Dasatinib is an orally active nonselective tyrosine kinase inhibitor used to treat certain types of adult leukemia. By inhibiting PDGFR-beta and SFKs in both tumor cells and tumor associated endothelial cells, dasatinib inhibits tumor growth and angiogenes ...

Amer Chemical Soc2015

Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity

Oliver Hantschel

Constitutive activation of the non-receptor tyrosine kinase c-Abl (cellular Abelson tyrosine protein kinase 1, Abl1) in the Bcr (breakpoint cluster region)-Abl1 fusion oncoprotein is the molecular cause of chronic myeloid leukaemia (CML). Recent studies ha ...

Portland Press2015

Safe Implementation of Embedded Software for a Portable Device Supporting Drug Administration

Giovanni De Micheli, Yann Thoma, Alena Simalatsar, Wenqi You Dubout

Poor adherence to medical regimen causes approximately 33% to 69% of medication-related hospitalizations and accounts for $100 billion in annual health care costs. In this paper we address the problem of unintentional non adherence, when patient fails to t ...

IEEE2014

Mechanisms of resistance to BCR-ABL and other kinase inhibitors

Oliver Hantschel, Allan Joaquim Lamontanara, Emel Basak Gencer Akçok, Orest Kuzyk

In this article, we are reviewing the molecular mechanisms that lead to kinase inhibitor resistance. As the oncogenic BCR-ABL kinase is the target of the first approved small-molecule kinase inhibitor imatinib, we will first focus on the structural and mec ...

Elsevier Science Bv2013

Parameterized SVM for Personalized Drug Concentration Prediction

Giovanni De Micheli, Alena Simalatsar, Wenqi You Dubout

This paper proposes a parameterized Support Vector Machine (ParaSVM) approach for modeling the Drug Concentration to Time (DCT) curves. It combines the merits of Support Vector Machine (SVM) algorithm that considers various patient features and an analytic ...

2013

TAT-based Formal Representation of Medical Guidelines : Imatinib Case-study

Giovanni De Micheli, Alena Simalatsar

Computer-based interpretation of medical guide- lines (GLs) has drawn lots of attention in the past three decades. It is essential to use a formalism for GLs representation that would enable the validation of GLs structural properties, be able to map medic ...

Ieee2012

Nilotinib as frontline and second-line therapy in chronic myeloid leukemia: open questions

Oliver Hantschel

Nilotinib is a second generation ABL tyrosine kinase inhibitor (TKI) that exerts major anti-leukemic effects in newly diagnosed patients with chronic myeloid leukemia (CML) as well as in most patients with imatinib-resistant CML. In freshly diagnosed patie ...

2012

BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia

Oliver Hantschel

Constitutive activation of STAT5 is critical for the maintenance of chronic myeloid leukemia (CML) characterized by the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (TKIs) for the STAT5-activating kinase JAK2 have been discussed as a treatment option fo ...

Nature Publishing Group2012

Structure, regulation, signaling, and targeting of abl kinases in cancer

Oliver Hantschel

Abl kinases are prototypic cytoplasmic tyrosine kinases and are involved in a variety of chromosomal aberrations in different cancers. This causes the expression of Abl fusion proteins, such as Bcr-Abl, that are constitutively activated and drivers of tumo ...

2012

A Drug Administration Decision Support System

Giovanni De Micheli, Alena Simalatsar, Wenqi You Dubout

Drug delivery is one of the most common clinical routines in hospitals, and is critical to patients’ health and recovery. It includes a decision making process in which a medical doctor decides the amount (dose) and frequency (dose interval) on the basis o ...

2012