Design Principles of Deep Pocket‐Targeting Protein Kinase Inhibitors

Backes, Alexander Christian; Müller, Gerhard; Sennhenn, Peter

doi:10.1002/9783527633470.ch6

Cited by 3 publications

(2 citation statements)

References 60 publications

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“…This mechanism of natural autoinhibition seen in ABL1 is lost upon fusion with the fragment of BCR which replaces the N-terminal cap region of ABL1 that contains the myristoylation site, thus leading to the constitutive activation of BCR-ABL1 . This assembled inactive state differs from the typical kinase inactive DFG-out conformation where ATP site directed type-II inhibitors stabilize the inactive conformation of the kinase domain by directly binding to the DFG-out loop conformation . Conceptually, a drug that inhibited ABL1 kinase by interacting with this myristoyl site would be more selective than ATP-competitive TKIs, would maintain activity against resistance mutations, and would not be subject to adverse events resulting from off-target kinase inhibition, and hence could be well tolerated.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1

et al. 2018

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Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.

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Section: Introductionmentioning

confidence: 99%

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1

et al. 2018

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“…These compounds exemplified by CHMFL-BMX-078 (8) showed high affinity for the inactive (nonphosphorylated) kinase while affinity for the active (phosphorylated) kinase was weak (apparent K d > 10 µM). It is assumed that the latter compound binds BMX and related kinases in a type II binding mode addressing the hydrophobic back-pocket sometimes referred to as "deep pocket" [30], which is only accessible in the DFG-out conformation. However, there is still a need for expanding the scope of novel BMX/TEC family kinase inhibitors with high selectivity or complementary selectivity patterns to study biology.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK

Förster

Liang

Schröder

et al. 2020

IJMS

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The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in the pathogenesis of diverse hematological malignancies. In contrast to the substantial efforts in inhibitor development for Bruton’s tyrosine kinase (BTK), specific inhibitors of the other TEC kinases, including the bone marrow tyrosine kinase on chromosome X (BMX), remain sparse. Here we present a novel class of dual BMX/BTK inhibitors, which were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket. Structure-guided design exploiting the differences in the gatekeeper residues enabled the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position. The most active compounds inhibited BMX and BTK with apparent IC50 values in the single digit nanomolar range or below showing moderate selectivity within the TEC family and potent cellular target engagement. These compounds represent an important first step towards selective chemical probes for the protein kinase BMX.

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Classical MD and metadynamics simulations on back-pocket binders of CDK2 and VEGFR2: a guidepost to design novel small-molecule dual inhibitors

Vásquez

Barrios

2021

Journal of Biomolecular Structure and Dynamics

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Design Principles of Deep Pocket‐Targeting Protein Kinase Inhibitors

Cited by 3 publications

References 60 publications

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1

Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK

Classical MD and metadynamics simulations on back-pocket binders of CDK2 and VEGFR2: a guidepost to design novel small-molecule dual inhibitors

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