An updated patent review of anaplastic lymphoma kinase inhibitors (2018-2022)

Review Biochemistry & Molecular Biology

Research Progress on the Drug Resistance of ALK Kinase Inhibitors

Zhen Li et al.

Summary: This article discusses the drug resistance of ALK inhibitors and introduces modified forms to overcome this resistance. It provides a theoretical basis for the development of the next generation of ALK kinase inhibitors.

CURRENT MEDICINAL CHEMISTRY (2022)

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Article Chemistry, Medicinal

Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations

Xile Liu et al.

Summary: ALK gene rearrangements are important oncogenic drivers in NSCLC. Crizotinib, a widely used first generation ALK inhibitor, has shown efficacy in ALK-positive lung cancer, but resistance remains a challenge. In this study, a novel inhibitor, WX-0593, was discovered and developed, which demonstrated potent activity against both wild type and resistant mutants of ALK in vitro and showed strong anti-tumor activity in a Crizotinib-resistant mouse model. WX-0593 is currently undergoing phase II/III clinical trials.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2022)

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Article Chemistry, Medicinal

Pyrizolo[1,5-a]pyrimidine derivatives of the second-generation TRK inhibitor: Design, synthesis and biological evaluation

Yiqing Fan et al.

Summary: As a key drug target in solid tumors, tropomyosin receptor kinase (Trk), a receptor tyrosine kinase (RTK), has been restricted in its use due to mutant drug resistance. However, the emergence of the Second-generation of Trk inhibitors, such as TPX-0005, has provided an effective solution to this resistance. In this study, a series of pyrizolo [1,5-a]pyrimidine derivatives were identified as second-generation Trk inhibitors, with compound 14h and 14j showing kinase activity comparable to TPX-0005 and higher selectivity of Trk inhibition.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2022)

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Article Oncology

Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models

Douglas D. Fang et al.

Summary: This study evaluates the preclinical efficacy of APG-2449 as a novel multikinase inhibitor. The results demonstrate that APG-2449 effectively inhibits cancer cell proliferation and exhibits potent antitumor activity in animal models. Furthermore, APG-2449 enhances the efficacy of other treatments and shows inhibitory effects on tumors that are insensitive to conventional drugs.

BMC CANCER (2022)

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Article Oncology

ALK plus Anaplastic Large Cell Lymphoma (ALCL)-Derived Exosomes Carry ALK Signaling Proteins and Interact with Tumor Microenvironment

Dimitrios Chioureas et al.

Summary: ALK+ anaplastic large cell lymphoma (ALK+ ALCL) is an aggressive non-Hodgkin lymphoma characterized by overexpression and activation of ALK kinase due to chromosomal translocations. This study demonstrates that ALK+ ALCL cells secrete exosomes containing critical components of ALK signaling which can be taken up by other cells, influencing tumor microenvironment and possibly contributing to treatment resistance. The interactions between ALK signaling and the microenvironment in ALK+ ALCL are not fully understood, but this research shows that exosome-mediated activation of stromal cells can alter the cytokine profile of the microenvironment, potentially impacting tumor aggressiveness and resistance to treatment.

CANCERS (2022)

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Article Chemistry, Medicinal

Fragment-based discovery of novel phenyltriazolyl derivatives as allosteric type-I1/2 ALK inhibitors with promising antitumor effects

Youbao Cui et al.

Summary: A series of phenyltriazolyl derivatives were developed based on the high-throughput screening hit BY-1. Among them, compound 12k exhibited excellent antitumor activities and promising inhibitory effects on ALK, making it a novel allosteric type-I1/2 ALK inhibitor.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2022)

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Article Oncology

First-in-human phase I study of TQ-B3139 (CT-711) in advanced non-small cell lung cancer patients with ALK and ROS1 rearrangements

Yuxiang Ma et al.

Summary: TQ-B3139 showed good tolerability and promising anti-tumor activities in patients with ALK and ROS1 positive advanced NSCLC, with better efficacy in TKI-naive patients.

EUROPEAN JOURNAL OF CANCER (2022)

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Article Medicine, General & Internal

Conteltinib (CT-707) in patients with advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, first-in-human phase 1 study

Puyuan Xing et al.

Summary: The study demonstrates that Conteltinib has favorable safety profile and anti-tumor activity in ALK-positive NSCLC patients. The recommended dose is 600 mg QD for ALK TKI-naive patients and 300 mg BID for patients who received crizotinib previously.

BMC MEDICINE (2022)

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Article Oncology

Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

Aya Shiba-Ishii et al.

Summary: This study identifies the spectrum of lorlatinib-resistant compound ALK mutations and identifies lorlatinib analogs that can overcome these compound mutations, providing different therapeutic strategies for precision targeting.

NATURE CANCER (2022)

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Article Pharmacology & Pharmacy

A multi-kinase inhibitor APG-2449 enhances the antitumor effect of ibrutinib in esophageal squamous cell carcinoma via EGFR/FAK pathway inhibition

Qiu-Yun Luo et al.

Summary: Esophageal squamous cell carcinoma (ESCC) is a common type of cancer in China with poor prognosis and lack of effective targeted therapy. A study found that the combination therapy of a novel multi-kinase inhibitor APG-2449 with ibrutinib showed strong synergistic antitumor effects in ESCC cell lines, inhibiting proliferation and migration, inducing cell cycle arrest and apoptosis. The combination therapy significantly down-regulated the phosphorylation levels of MEK/ERK and AKT, providing a potential effective therapeutic strategy for ESCC patients.

BIOCHEMICAL PHARMACOLOGY (2021)

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Article Oncology

Will the clinical development of 4th-generation double mutant active ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK plus NSCLC?

Sai-Hong Ignatius Ou et al.

Summary: The current treatment paradigm for advanced ALK+ NSCLC classifies ALK TKIs into three generations, but there are now fourth generation double mutant active ALK TKIs. The success of 4G ALK TKIs will depend on specific properties and clinical trial designs tailored for their use, potentially ushering in a new treatment paradigm based on functional capabilities rather than generational classification.

TRANSLATIONAL ONCOLOGY (2021)

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Article Oncology

TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations

Brion W. Murray et al.

Summary: TPX-0131 is a compact macrocyclic molecule designed to inhibit ALK fusion proteins, showing higher potency against a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, compared to current approved ALK inhibitors.

MOLECULAR CANCER THERAPEUTICS (2021)

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Article Oncology

ALKAL1 gene silencing prevents colorectal cancer progression via suppressing Sonic Hedgehog (SHH) signaling pathway

Shasha Chen et al.

Summary: ALKAL1 is upregulated in colorectal cancer tissues and cell lines, and its high expression is associated with tumor malignancy and poor prognosis. Silencing of ALKAL1 inhibits tumorigenesis, metastasis, and invasion of colorectal cancer cells by suppressing the SHH signaling pathway.

JOURNAL OF CANCER (2021)

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Article Biochemistry & Molecular Biology

Design, synthesis and biological evaluation of 2-arylaminopyrimidine derivatives bearing 1,3,8-triazaspiro[4,5]decan-4-one or piperidine-3-carboxamide moiety as novel Type-I1/2 ALK inhibitors

Xiuqi Miao et al.

BIOORGANIC CHEMISTRY (2020)

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Review Chemistry, Medicinal

Anaplastic lymphoma kinase inhibitors: an updated patent review (2014-2018)

Yi-Min Liu et al.

EXPERT OPINION ON THERAPEUTIC PATENTS (2020)

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Article Oncology

Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study

T. Mok et al.

ANNALS OF ONCOLOGY (2020)

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Article Oncology

A phase I study to evaluate safety, tolerability, pharmacokinetics, and preliminary antitumor activity of TQ-B3101.

Yong Fang et al.

JOURNAL OF CLINICAL ONCOLOGY (2020)

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Meeting Abstract Oncology

TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitors

J. Jean Cui et al.

CANCER RESEARCH (2020)

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Article Chemistry, Medicinal

Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

Xiaotian Kong et al.

JOURNAL OF MEDICINAL CHEMISTRY (2019)

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Article Oncology

476PUpdated efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: Integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001

C Rolfo et al.

ANNALS OF ONCOLOGY (2019)

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Article Oncology

CT-707 Overcomes Resistance of Crizotinib through Activating PDPK1-AKT1 Pathway by Targeting FAK

Caixia Liang et al.

CURRENT CANCER DRUG TARGETS (2019)

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Article Oncology

Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study

Leora Horn et al.

CLINICAL CANCER RESEARCH (2018)

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Review Chemistry, Medicinal

Dual or multi-targeting inhibitors: The next generation anticancer agents

Nulgumnalli Manjunathaiah Raghavendra et al.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Article Oncology

Background and rationale of the eXalt3 tria investigating X-396 in the treatment of ALK plus non-small-cell lung cancer

Eric K. Singhi et al.

FUTURE ONCOLOGY (2018)

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Article Chemistry, Medicinal

Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

Chelsea E. Powell et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Article Oncology

Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer

Satoshi Yoda et al.

CANCER DISCOVERY (2018)

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Review Health Care Sciences & Services

Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors

Dazhi Liu et al.

THERAPEUTICS AND CLINICAL RISK MANAGEMENT (2018)

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Article Oncology

Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibit ROS1/TRK/ALK Solvent-Front Mutations

Alexander Drilon et al.

CANCER DISCOVERY (2018)

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Article Oncology

Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study

Benjamin J. Solomon et al.

LANCET ONCOLOGY (2018)

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Meeting Abstract Oncology

TPX-0005, a polypharmacology inhibitor, overcomes ALK treatment resistance from acquired mutations, bypass signaling, and EMT

Dayong Zhai et al.

MOLECULAR CANCER THERAPEUTICS (2018)

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Review Chemistry, Medicinal

First macrocyclic 3rd-generation ALK inhibitor for treatment of ALK/ROS1 cancer: Clinical and designing strategy update of lorlatinib

Sulman Basit et al.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2017)

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Article Medicine, General & Internal

First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study

Jean-Charles Soria et al.

LANCET (2017)

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Article Oncology

Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial

Alice T. Shaw et al.

LANCET ONCOLOGY (2017)

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Article Multidisciplinary Sciences

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib

Thomas Lee Collier et al.

NATURE COMMUNICATIONS (2017)

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Article Oncology

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)

Alexander Drilon et al.

CANCER DISCOVERY (2017)

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Article Chemistry, Multidisciplinary

Combating Drug-Resistant Mutants of Anaplastic Lymphoma Kinase with Potent and Selective Type-I1/2 Inhibitors by Stabilizing Unique DFG-Shifted Loop Conformation

Peichen Pan et al.

ACS CENTRAL SCIENCE (2017)

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Article Oncology

The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models

Sen Zhang et al.

CLINICAL CANCER RESEARCH (2016)

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Article Oncology

FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib

Erin Larkins et al.

CLINICAL CANCER RESEARCH (2016)

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Review Oncology

Central nervous system involvement in ALK-rearranged NSCLC: promising strategies to overcome crizotinib resistance

Alessandro Russo et al.

EXPERT REVIEW OF ANTICANCER THERAPY (2016)

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Article Oncology

Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2

Lucio Crino et al.

JOURNAL OF CLINICAL ONCOLOGY (2016)

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Article Oncology

Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study

Sai-Hong Ignatius Ou et al.

JOURNAL OF CLINICAL ONCOLOGY (2016)

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Article Chemistry, Medicinal

Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK)

Chih-Hsiang Tu et al.

JOURNAL OF MEDICINAL CHEMISTRY (2016)

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Article Chemistry, Medicinal

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase

Wei-Sheng Huang et al.

JOURNAL OF MEDICINAL CHEMISTRY (2016)

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Meeting Abstract Oncology

Whole Body and Intracranial Efficacy of Ceritinib in ALK-inhibitor Naive Patients with ALK plus NSCLC and Brain Metastases: Results of ASCEND 1 and 3

Alice T. Shaw et al.

JOURNAL OF THORACIC ONCOLOGY (2016)

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Article Oncology

Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Elena Ardini et al.

MOLECULAR CANCER THERAPEUTICS (2016)

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Review Oncology

Anaplastic lymphoma kinase: Role in cancer and therapy perspective

Zhihong Zhao et al.

CANCER BIOLOGY & THERAPY (2015)

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Meeting Abstract Oncology

STARTRK-1: Phase 1/2a study of entrectinib, an oral Pan-Trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations.

Manish R. Patel et al.

JOURNAL OF CLINICAL ONCOLOGY (2015)

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Meeting Abstract Oncology

Alka-372-001: First-in-human, phase I study of entrectinib - an oral pan-trk, ROS1, and ALK inhibitor - in patients with advanced solid tumors with relevant molecular alterations.

Filippo G. De Braud et al.

JOURNAL OF CLINICAL ONCOLOGY (2015)

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Article Oncology

Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases

Tatsushi Kodama et al.

CANCER CHEMOTHERAPY AND PHARMACOLOGY (2014)

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Review Chemistry, Medicinal

Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review

Eugen F. Mesaros et al.

EXPERT OPINION ON THERAPEUTIC PATENTS (2014)

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Review Chemistry, Medicinal

Deuterated drugs: where are we now?

Graham S. Timmins

EXPERT OPINION ON THERAPEUTIC PATENTS (2014)

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Article Chemistry, Medicinal

Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

Ted W. Johnson et al.

JOURNAL OF MEDICINAL CHEMISTRY (2014)

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Article Medicine, General & Internal

First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer

Benjamin J. Solomon et al.

NEW ENGLAND JOURNAL OF MEDICINE (2014)

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Article Oncology

The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non-Small Cell Lung Cancer

Luc Friboulet et al.

CANCER DISCOVERY (2014)

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Article Medicine, General & Internal

Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer

Alice T. Shaw et al.

NEW ENGLAND JOURNAL OF MEDICINE (2013)

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Article Chemistry, Medicinal

Boron-Containing Compounds as Preventive and Chemotherapeutic Agents for Cancer

Romulus I. Scorei et al.

Anti-Cancer Agents in Medicinal Chemistry (2012)

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Article Oncology

Anaplastic Lymphoma Kinase Aberrations in Rhabdomyosarcoma: Clinical and Prognostic Implications

J. Carlijn van Gaal et al.

JOURNAL OF CLINICAL ONCOLOGY (2012)

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Article Multidisciplinary Sciences

Inhibition of Anaplastic Lymphoma Kinase (ALK) Activity Provides a Therapeutic Approach for CLTC-ALK-Positive Human Diffuse Large B Cell Lymphomas

Leandro Cerchietti et al.

PLOS ONE (2011)

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Article Biochemistry & Molecular Biology

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

Christian C. Lee et al.

BIOCHEMICAL JOURNAL (2010)

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Article Biochemistry & Molecular Biology

Cell Signaling by Receptor Tyrosine Kinases

Mark A. Lemmon et al.

CELL (2010)

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Article Oncology

Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma Patients

Lorena Passoni et al.

CANCER RESEARCH (2009)

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Review Oncology

Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy

Thomas R. Webb et al.

EXPERT REVIEW OF ANTICANCER THERAPY (2009)

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Article Multidisciplinary Sciences

Identification of ALK as a major familial neuroblastoma predisposition gene

Yael P. Mosse et al.

NATURE (2008)

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Article Biochemistry & Molecular Biology

Characterization of some molecular mechanisms governing autoactivation of the catalytic domain of the anaplastic lymphoma kinase

Carmen J. Tartari et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2008)

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Review Oncology

The anaplastic lymphoma kinase in the pathogenesis of cancer

Roberto Chiarle et al.

NATURE REVIEWS CANCER (2008)

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Article Multidisciplinary Sciences

Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer

Manabu Soda et al.

NATURE (2007)

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Article Multidisciplinary Sciences

Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism

Alexandr P. Kornev et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2006)

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Article Pathology

ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor

CM Coffin et al.

MODERN PATHOLOGY (2001)

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Article Pathology

Expression of the ALK tyrosine kinase gene in neuroblastoma

L Lamant et al.

AMERICAN JOURNAL OF PATHOLOGY (2000)

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An updated patent review of anaplastic lymphoma kinase inhibitors (2018-2022)

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