scholarly journals Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuai Liang ◽  
Qing Wang ◽  
Xuesen Qi ◽  
Yudi Liu ◽  
Guozhen Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Targeted Therapies ◽  
Anaplastic Lymphoma Kinase ◽  
Double Mutant ◽  
Conformational Dynamics ◽  
Bound State ◽  
Kinase Domain ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Dynamics Simulations

Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in NSCLC.

scholarly journals Brigatinib versus other second-generation ALK inhibitors as initial treatment of anaplastic lymphoma kinase positive non-small cell lung cancer with deep phenotyping: study protocol of the ABP trial

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Petros Christopoulos ◽  
Farastuk Bozorgmehr ◽  
Lena Brückner ◽  
Inn Chung ◽  
Johannes Krisam ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Anaplastic Lymphoma Kinase ◽  
Second Generation ◽  
Search Query ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Link Type ◽  
Biomarker Analysis ◽  
Nsclc Patients

Abstract Background Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. Methods/design In this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. Discussion Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a “chronic disease” will be distinguished from “high-risk” cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. Trial registration Clinicaltrials.gov, NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019–001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36

scholarly journals Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1427
Author(s):  
Annette K. Brenner ◽  
Maria W. Gunnes
Keyword(s):  
Drug Resistance ◽  
Nervous System ◽  
Cancer Cells ◽  
Anaplastic Lymphoma Kinase ◽  
Signalling Pathways ◽  
Special Focus ◽  
Clinical Use ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Wide Range

Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment regimens are probably less likely to induce drug resistance, a special focus will be on the combination of ALK inhibitors with drugs that either target downstream signalling pathways or that affect the survival and proliferation of cancer cells in general.

Discovery of novel anaplastic lymphoma kinase inhibitors: Structure and energy-based pharmacophore strategy

2019 ◽  
Vol 18 (03) ◽  
pp. 1950014 ◽  
Author(s):  
Nivya James ◽  
V. Shanthi ◽  
K. Ramanathan
Keyword(s):  
Lung Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Density Functional ◽  
Kinase Inhibitors ◽  
Chemical Reactivity ◽  
Pharmacophore Model ◽  
Density Functional Theory Calculations ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Glide Docking

The clinical outcomes in patients with non-small cell lung cancer have improved, as a result of anaplastic lymphoma kinase (ALK) inhibition. Therefore in the current study, substantial effort has been made to identify ALK inhibitors through systematic virtual screening experiment consisting of e-pharmacophore and pharmacophore perception techniques. Initially, a pharmacophore model (AAAHP.193) and an e-pharmacophore model (DDRRR) encompassing the whole dataset of 12 known ALK inhibitors were developed. The hypotheses could retrieve effective compounds from DrugBank database (8621 molecules), which were then subjected to molecular docking and ADME prediction. These approaches resulted in the identification of five hits, namely, nebivolol, HDY, D42, 796, and LZE having higher Glide docking scores and promising ADME properties with augmented CNS involvement. Moreover, molecular dynamics simulations were performed to validate the inhibitory activity of the hit compounds, and density functional theory calculations were carried out to scrutinize the chemical reactivity of the hits. Subsequent interaction and scaffold analysis identified prominent interactions of the hits with ALK kinase domain and scaffolds with anti-tumor activity against lung cancer cell lines. We strongly believe that the study provides an outlook for the sighting of novel and potent ALK inhibitors in the near future.

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.

Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: Wild type and mutant (L1196M) active compounds with unique binding mode

2013 ◽  
Vol 23 (17) ◽  
pp. 4911-4918 ◽  
Author(s):  
Venkateshwar Rao Gummadi ◽  
Sujatha Rajagopalan ◽  
Chung-Yeng Looi ◽  
Mohammadjavad Paydar ◽  
Girish Aggunda Renukappa ◽  
...  
Keyword(s):  
Anaplastic Lymphoma Kinase ◽  
Binding Mode ◽  
Wild Type ◽  
Active Compounds ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma

scholarly journals Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2

2020 ◽  
Author(s):  
Sven H. Schmidt ◽  
Jui-Hung Weng ◽  
Phillip C. Aoto ◽  
Daniela Boassa ◽  
Sebastian Mathea ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Conformational Dynamics ◽  
Subcellular Location ◽  
Kinase Domain ◽  
Activation Process ◽  
Type I ◽  
Rab Gtpases ◽  
Exchange Mass Spectrometry ◽  
Catalytic Domains ◽  
Dynamics Simulations

AbstractIn a multi-tiered approach, we explored how Parkinson’s Disease-related mutations hijack the finely tuned activation process of Leucine-Rich Repeat Kinase 2 (LRRK2) using a construct containing the ROC, Cor, Kinase and WD40 domains (LRRK2RCKW). We hypothesized that the N-terminal domains shield the catalytic domains in an inactive state. PD mutations, type-I LRRK2 inhibitors, or physiological Rab GTPases can unleash the catalytic domains while the active kinase conformation, but not kinase activity, is essential for docking onto microtubules. Mapping solvent accessible regions of LRRK2RCKW employing hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed how inhibitor binding is sensed by the entire protein. Molecular Dynamics simulations of the kinase domain elucidated differences in conformational dynamics between wt and mutants of the DYGψ motif. While all domains contribute to regulating kinase activity and spatial distribution, the kinase domain, driven by the DYGψ motif, coordinates domain crosstalk and serves as an intrinsic hub for LRRK2 regulation.

scholarly journals Differences in the dynamics of the tandem-SH2 modules of the Syk and ZAP-70 tyrosine kinases

2021 ◽  
Author(s):  
Helen T. Hobbs ◽  
Neel H. Shah ◽  
Jean M. Badroos ◽  
Christine L. Gee ◽  
Susan Marqusee ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Tyrosine Kinases ◽  
Bound State ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Hydrogen Deuterium Exchange ◽  
Inactive Conformation ◽  
Downstream Signaling ◽  
Hydrogen Deuterium ◽  
Dynamics Simulations

The catalytic activity of Syk-family tyrosine kinases is regulated by a tandem-SH2 module (tSH2 module). In the autoinhibited state, this module adopts a conformation which stabilizes an inactive conformation of the kinase domain. The binding of the tSH2 module to doubly-phosphorylated tyrosine-containing motifs necessitates a conformational change, thereby relieving kinase inhibition and promoting activation. We determined the crystal structure of the isolated tSH2 module of Syk and find, in contrast to ZAP-70, that its conformation more closely resembles that of the peptide-bound state, rather than the autoinhibited state. Hydrogen-deuterium exchange by mass spectrometry, as well as molecular dynamics simulations, reveal that the dynamics of the tSH2 modules of Syk and ZAP-70 differ, with most of these differences occurring in the C-terminal SH2 domain. Our data suggest that the conformational landscapes of the tSH2 modules in Syk and ZAP-70 have been tuned differently, such that the auto-inhibited conformation of the Syk tSH2 module is less stable. This feature of Syk likely contributes to its ability to more readily escape autoinhibition when compared to ZAP-70, consistent with tighter control of downstream signaling pathways in T cells.

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