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

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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

γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia

Oliver Hantschel, Anja Irmisch

The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ ...

2019

Cytosolic delivery and characterization of monobodies interfering with SH2 domain-phosphotyrosine interactions

Nadine Eliane Schmit

Targeted cancer therapy is a very promising concept; however, small molecule inhibitors only exist for a limited number of oncoproteins and resistance development limits their clinical use. Different engineered non-antibody scaffolds are being explored to ...

EPFL2018

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

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

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

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The two major isoforms of the oncogenic Bcr-Abl tyrosine kinase, p210 and p190, are expressed upon the Philadelphia chromosome translocation. p210 is the hallmark of chronic myelogenous leukemia, whereas p190 occurs in the majority of B-cell acute lymphobl ...

Nature Publishing Group2017

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

HRD Motif as the Central Hub of the Signaling Network for Activation Loop Autophosphorylation in Abl Kinase

Andrea Cavalli, Oliver Hantschel, Grégory La Sala

A number of structural factors modulate the activity of Abelson (Abl) tyrosine kinase, whose deregulation is often related to oncogenic processes. First, only the open conformation of the Abl kinase domain's activation loop (A-loop) favors ATP binding to t ...

Amer Chemical Soc2016

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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

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