scholarly journals Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase: A Catalytic Receptor with Many Faces

2018 ◽  
Vol 19 (11) ◽  
pp. 3448 ◽  
Author(s):  
Hao Huang
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Fusion Proteins ◽  
Point Mutations ◽  
Clinical Applications ◽  
Significant Progress ◽  
Significant Information ◽  
Anaplastic Lymphoma ◽  
Membrane Bound

The anaplastic lymphoma kinase (ALK) receptor is a membrane-bound tyrosine kinase. The pathogenesis of several cancers is closely related to aberrant forms of ALK or aberrant ALK expression, including ALK fusion proteins, ALK-activated point mutations, and ALK amplification. Clinical applications of different ALK inhibitors represent significant progress in targeted therapy. Knowledge of different aspects of ALK biology can provide significant information to further the understanding of this receptor tyrosine kinase. In this mini-review, we briefly summarize different features of ALK. We also summarize some recent research advances on ALK fusion proteins in cancers.

scholarly journals 4558 Investigating the functional consequences of anaplastic lymphoma kinase (ALK) mutations arising upon Lorlatinib treatment

2020 ◽  
Vol 4 (s1) ◽  
pp. 9-10
Author(s):  
Gabriela Maria Witek ◽  
Whelton Miller ◽  
David Slochower ◽  
Esther Berko ◽  
Yael Mossé ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
De Novo ◽  
Point Mutations ◽  
Md Simulations ◽  
Competitive Inhibitor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Anaplastic Lymphoma ◽  
Mechanism Of Resistance

OBJECTIVES/GOALS: Neuroblastoma (NB) is an embryonal cancer of the sympathetic nervous system that affects mostly infants and young children. The complex genetic background present across NB patients results in diverse clinical response and difficulty in individualizing therapy. Currently, NB patients undergo a regimen of genotoxic chemotherapeutics, radiation therapy, and new immunotherapy that, while effective, has significant side effects, including excruciating pain. One promising avenue for targeted therapy in neuroblastoma focuses on anaplastic lymphoma kinase (ALK), a cell surface neural receptor tyrosine kinase. We previously identified activating point mutations within the tyrosine kinase domain of ALK as the primary cause of hereditary NB, and we and others subsequently showed that these same alterations are the most common somatic single-nucleotide mutations in the sporadic forms of the disease. Crizotinib, a first-generation small molecule ATP-competitive inhibitor of the ALK tyrosine kinase, showed limited anti-tumor activity in patients with relapsed NB harboring ALK F1174 and F1245 mutations. We have demonstrated that lorlatinib, a novel ATP-competitive ALK inhibitor, overcomes this de novo resistance in preclinical models of ALK-driven NB. Recent clinical trials with lorlatinib in patients with non-small cell lung cancer harboring an ALK fusion, and in patients with NB harboring ALK mutations show the emergence of multiple or compound ALK mutations as a mechanism of resistance. We postulate that these compound mutations disrupt the interaction between and ALK and cause resistance. In this study, we employ a computational approach to model mutated ALK in complex with lorlatinib as well as ATP to understand whether the new mutations alter the affinity or mode of lorlatinib/ATP binding to ALK, and thus cause suboptimal ALK inhibition. METHODS/STUDY POPULATION: We employ methods in computational structural biology and drug design, primarily based on molecular modeling, molecular dynamics (MD), and molecular docking. Based on existing crystal structures of wildtype ALK, we model the mutations and perform MD simulations in order to characterize the activation state of the protein as well as perform ensemble docking calculations to assess the binding affinities and modes in ALK-lorlatinib and ALK-ATP complexes. RESULTS/ANTICIPATED RESULTS: We expect that the compound mutations cause resistance to lorlatinib either by lowering protein affinity for the drug or increasing the affinity for ATP. Alternatively, the compound mutations may disrupt the protein activation state, in which case ALK may no longer be active, and another protein/pathway could be driving the resistance. DISCUSSION/SIGNIFICANCE OF IMPACT: The results of this study will enable the understanding of the mechanism of resistance to lorlatinib and facilitate the design of new ALK inhibitors, or help develop more optimal and mechanism-guided therapies aimed to overcome the resistance.

scholarly journals Activation and Inhibition of Anaplastic Lymphoma Kinase Receptor Tyrosine Kinase by Monoclonal Antibodies and Absence of Agonist Activity of Pleiotrophin

2005 ◽  
Vol 280 (28) ◽  
pp. 26039-26048 ◽  
Author(s):  
Christel Moog-Lutz ◽  
Joffrey Degoutin ◽  
Jean Y. Gouzi ◽  
Yvelyne Frobert ◽  
Nicole Brunet-de Carvalho ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Agonist Activity ◽  
Anaplastic Lymphoma

scholarly journals A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster

EMBO Reports ◽  
2003 ◽  
Vol 4 (8) ◽  
pp. 781-786 ◽  
Author(s):  
Christina E Lorén ◽  
Camilla Englund ◽  
Caroline Grabbe ◽  
Bengt Hallberg ◽  
Tony Hunter ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Crucial Role ◽  
Gut Development ◽  
Anaplastic Lymphoma

Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain

2010 ◽  
Vol 430 (3) ◽  
pp. 425-437 ◽  
Author(s):  
Christian C. Lee ◽  
Yong Jia ◽  
Nanxin Li ◽  
Xiuying Sun ◽  
Kenneth Ng ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Catalytic Domain ◽  
Peptide Binding ◽  
Kinase Domain ◽  
Full Length ◽  
Receptor Kinase ◽  
Anaplastic Lymphoma

ALK (anaplastic lymphoma kinase) is an RTK (receptor tyrosine kinase) of the IRK (insulin receptor kinase) superfamily, which share an YXXXYY autophosphorylation motif within their A-loops (activation loops). A common activation and regulatory mechanism is believed to exist for members of this superfamily typified by IRK and IGF1RK (insulin-like growth factor receptor kinase-1). Chromosomal translocations involving ALK were first identified in anaplastic large-cell lymphoma, a subtype of non-Hodgkin's lymphoma, where aberrant fusion of the ALK kinase domain with the NPM (nucleophosmin) dimerization domain results in autophosphosphorylation and ligand-independent activation. Activating mutations within the full-length ALK kinase domain, most commonly R1275Q and F1174L, which play a major role in neuroblastoma, were recently identified. To provide a structural framework for understanding these mutations and to guide structure-assisted drug discovery efforts, the X-ray crystal structure of the unphosphorylated ALK catalytic domain was determined in the apo, ADP- and staurosporine-bound forms. The structures reveal a partially inactive protein kinase conformation distinct from, and lacking, many of the negative regulatory features observed in inactive IGF1RK/IRK structures in their unphosphorylated forms. The A-loop adopts an inhibitory pose where a short proximal A-loop helix (αAL) packs against the αC helix and a novel N-terminal β-turn motif, whereas the distal portion obstructs part of the predicted peptide-binding region. The structure helps explain the reported unique peptide substrate specificity and the importance of phosphorylation of the first A-loop Tyr1278 for kinase activity and NPM–ALK transforming potential. A single amino acid difference in the ALK substrate peptide binding P−1 site (where the P-site is the phosphoacceptor site) was identified that, in conjunction with A-loop sequence variation including the RAS (Arg-Ala-Ser)-motif, rationalizes the difference in the A-loop tyrosine autophosphorylation preference between ALK and IGF1RK/IRK. Enzymatic analysis of recombinant R1275Q and F1174L ALK mutant catalytic domains confirms the enhanced activity and transforming potential of these mutants. The transforming ability of the full-length ALK mutants in soft agar colony growth assays corroborates these findings. The availability of a three-dimensional structure for ALK will facilitate future structure–function and rational drug design efforts targeting this receptor tyrosine kinase.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery

2020 ◽  
Vol 17 (5) ◽  
pp. 585-615 ◽  
Author(s):  
Nikhil S. Sakle ◽  
Shweta A. More ◽  
Sachin A. Dhawale ◽  
Santosh N. Mokale
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Cell Functions ◽  
Anaplastic Lymphoma

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

scholarly journals Only the Substitution of Methionine 918 with a Threonine and Not with Other Residues Activates RET Transforming Potential*

Endocrinology ◽  
1997 ◽  
Vol 138 (4) ◽  
pp. 1450-1455 ◽  
Author(s):  
Anna Maria Cirafici ◽  
Giuliana Salvatore ◽  
Gabriella De Vita ◽  
Francesca Carlomagno ◽  
Nina A. Dathan ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Point Mutations ◽  
Early Response ◽  
Specific Point ◽  
Medullary Thyroid ◽  
Transforming Activity ◽  
Early Response Genes

Abstract Specific point-mutations of the RET receptor tyrosine kinase protooncogene are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). MEN2B is caused by the substitution of methionine 918 by a threonine in the tyrosine kinase (TK) domain of RET. This mutation converts RET into a dominant transforming oncogene. We have substituted Met918 with four different residues and found that RET acquired transforming activity only when Met918 was substituted with a threonine. However, also when serine and valine, but not leucine or phenylalanine, were inserted in position 918, the RET TK function was activated and induced, especially in the case of the RET(918Ser), immmediate-early response genes. We conclude that the preservation of Met918 is critical for the control of RET kinase. However, only when a threonine residue is present in position 918, does RET efficiently couple with a transforming pathway.

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