ALK receptor tyrosine kinase | Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family | IUPHAR/BPS Guide to PHARMACOLOGY

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ALK receptor tyrosine kinase

Target not currently curated in GtoImmuPdb

Target id: 1839

Nomenclature: ALK receptor tyrosine kinase

Abbreviated Name: ALK

Family: Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1620 2p23 ALK ALK receptor tyrosine kinase
Mouse 1 1621 17 Alk anaplastic lymphoma kinase
Rat - 1617 6q13 Alk ALK receptor tyrosine kinase
Previous and Unofficial Names
CD246 | ALK tyrosine kinase receptor | Tcrz | anaplastic lymphoma receptor tyrosine kinase
Database Links
BRENDA
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of anaplastic lymphoma kinase complexed with LDK378.
PDB Id:  4MKC
Ligand:  ceritinib
Resolution:  2.01Å
Species:  Human
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the human anaplastic lymphoma kinase in complex with crizotinib (PF-02341066).
PDB Id:  2XP2
Ligand:  crizotinib
Resolution:  1.9Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Structure of L1196M mutant anaplastic lymphoma kinase in complex with crizotinib. The L1196M mutation is in the gatekeeper residue, which in the wild-type kinase controls access to the ATP binding pocket of the enzyme. The mutation inhibits drug access to the ATP binding pocket.
PDB Id:  2YFX
Ligand:  crizotinib
Resolution:  1.7Å
Species:  Human
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  Structure of L1196M mutant human Anaplastic Lymphoma Kinase in complex with PF-06463922. It is important to note that this compound binds to this gatekeeper mutant and so will be active in drug-resistant tumours carrying this mutation.
PDB Id:  4CLJ
Ligand:  lorlatinib
Resolution:  1.66Å
Species:  Human
References:  11
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human anaplastic lymphoma kinase in complex with acyliminobenzimidazole inhibitor 36
PDB Id:  4FOD
Ligand:  belizatinib
Resolution:  2.0Å
Species:  Human
References:  15
Enzyme Reaction
EC Number: 2.7.10.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
belizatinib Hs Inhibition 9.4 pKd 15
pKd 9.4 (Kd 3.6x10-10 M) [15]
Description: Binding affinity in vitro.
NVP-TAE684 Hs Inhibition 9.0 pKd 4
pKd 9.0 (Kd 1.1x10-9 M) [4]
brigatinib Hs Inhibition 10.1 pKi 12
pKi 10.1 (Ki 9x10-11 M) [12]
Description: Wild type ALK
lorlatinib Hs Inhibition 9.1 pKi 11
pKi 9.1 (Ki 7x10-10 M) [11]
Description: Note that this is inhibition of the ALK L1196M mutant enzyme.
ceritinib Hs Inhibition 9.7 pIC50 17
pIC50 9.7 (IC50 2x10-10 M) [17]
ensartinib Hs Inhibition >9.4 pIC50 16
pIC50 >9.4 (IC50 <4x10-10 M) [16]
Description: Result from DiscoveRx KINOMEscan® selectivity screen.
brigatinib Hs Inhibition 9.2 – 9.4 pIC50 10,12
pIC50 9.2 – 9.4 (IC50 6.2x10-10 – 3.7x10-10 M) [10,12]
GSK-1838705A Hs Inhibition 9.3 pIC50 22
pIC50 9.3 (IC50 5x10-10 M) [22]
gilteritinib Hs Inhibition ~9.3 pIC50 14
pIC50 ~9.3 (IC50 ~5x10-10 M) [14]
TL13-112 Hs Inhibition 9.2 pIC50 21
pIC50 9.2 (IC50 6x10-10 M) [21]
Description: Determined in a biochemical kinase activity assay.
compound 8e [PMID: 24432909] Hs Inhibition 9.1 pIC50 9
pIC50 9.1 (IC50 8x10-10 M) [9]
crizotinib Hs Inhibition 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3]
TPX-0005 Hs Inhibition 9.0 pIC50 5
pIC50 9.0 (IC50 1.04x10-9 M) IC50 for ALKG1202R is 1.2 nM. [5]
alectinib Hs Inhibition 8.7 pIC50 13
pIC50 8.7 (IC50 1.9x10-9 M) [13]
compound 25b [PMID: 22564207] Hs Inhibition 8.7 pIC50 8
pIC50 8.7 (IC50 1.9x10-9 M) [8]
CEP-37440 Hs Inhibition 8.5 pIC50 19
pIC50 8.5 (IC50 3.1x10-9 M) [19]
AZD3463 Hs Inhibition >8.0 pIC50 2
pIC50 >8.0 (IC50 <1x10-8 M) [2]
compound 5m [PMID: 20483621] Hs Inhibition 8.0 pIC50 18
pIC50 8.0 (IC50 1x10-8 M) [18]
compound 5n [PMID: 20483621] Hs Inhibition 8.0 pIC50 18
pIC50 8.0 (IC50 1x10-8 M) [18]
compound 5g [PMID: 20483621] Hs Inhibition 8.0 pIC50 18
pIC50 8.0 (IC50 1.1x10-8 M) [18]
compound 15 [PMID: 24900237] Hs Inhibition 7.8 pIC50 20
pIC50 7.8 (IC50 1.4x10-8 M) [20]
Inhibitor Comments
The Ki for brigatinib (AP26113) vs ALK carrying the L1196M gatekeeper mutation is 0.08nM [12].
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 4,23

Key to terms and symbols Click column headers to sort
Target used in screen: ALK
Ligand Sp. Type Action Value Parameter
GSK-1838705A Hs Inhibitor Inhibition 9.3 pKd
NVP-TAE684 Hs Inhibitor Inhibition 9.0 pKd
crizotinib Hs Inhibitor Inhibition 8.5 pKd
staurosporine Hs Inhibitor Inhibition 7.5 pKd
foretinib Hs Inhibitor Inhibition 7.2 pKd
lestaurtinib Hs Inhibitor Inhibition 7.2 pKd
BI-2536 Hs Inhibitor Inhibition 6.8 pKd
sunitinib Hs Inhibitor Inhibition 6.8 pKd
tamatinib Hs Inhibitor Inhibition 6.6 pKd
midostaurin Hs Inhibitor Inhibition 6.6 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,7

Key to terms and symbols Click column headers to sort
Target used in screen: ALK/ALK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 0.9 0.0 0.5
SU11652 Hs Inhibitor Inhibition 3.5 8.0 2.0
K-252a Hs Inhibitor Inhibition 10.7 10.0 1.0
Gö 6976 Hs Inhibitor Inhibition 12.2 0.0 4.0
JAK3 inhibitor II Hs Inhibitor Inhibition 12.5 19.0 3.0
sunitinib Hs Inhibitor Inhibition 16.6
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 16.7 16.0 1.0
JAK inhibitor I Hs Inhibitor Inhibition 20.0 30.0 11.0
SB 218078 Hs Inhibitor Inhibition 36.9 81.0 79.0
indirubin derivative E804 Hs Inhibitor Inhibition 38.1 24.0 2.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  ALK-positive anaplastic large cell lymphoma
Synonyms: Anaplastic large cell lymphoma [Disease Ontology: DOID:0050744]
Disease Ontology: DOID:0050744
Orphanet: ORPHA300895
Disease:  ALK-positive large B-cell lymphoma
Orphanet: ORPHA364043
Disease:  Inflammatory myofibroblastic tumor
Orphanet: ORPHA178342
Disease:  Neuroblastoma, susceptibility to, 3; NBLST3
Synonyms: Neuroblastoma [Orphanet: ORPHA635] [Disease Ontology: DOID:769]
Disease Ontology: DOID:769
OMIM: 613014
Orphanet: ORPHA635

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. AstraZeneca. AZD3463. Accessed on 11/09/2014. Modified on 11/09/2014. astrazeneca.com, http://openinnovation.astrazeneca.com/what-we-offer/compound/azd3463/

3. Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I et al.. (2011) Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J. Med. Chem., 54 (18): 6342-63. [PMID:21812414]

4. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

5. Drilon A, Ou SI, Cho BC, Kim DW, Lee J, Lin JJ, Zhu VW, Ahn MJ, Camidge DR, Nguyen J et al.. (2018) Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer Discov, 8 (10): 1227-1236. [PMID:30093503]

6. Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, Michellys PY, Awad MM, Yanagitani N, Kim S et al.. (2014) The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov, 4 (6): 662-673. [PMID:24675041]

7. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

8. Gingrich DE, Lisko JG, Curry MA, Cheng M, Quail M, Lu L, Wan W, Albom MS, Angeles TS, Aimone LD et al.. (2012) Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J. Med. Chem., 55 (10): 4580-93. [PMID:22564207]

9. Huang Q, Johnson TW, Bailey S, Brooun A, Bunker KD, Burke BJ, Collins MR, Cook AS, Cui JJ, Dack KN et al.. (2014) Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J. Med. Chem., 57 (4): 1170-87. [PMID:24432909]

10. Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J et al.. (2016) Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J. Med. Chem., 59 (10): 4948-64. [PMID:27144831]

11. Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, Cui JJ, Deal JG, Deng YL, Dinh D et al.. (2014) 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. J. Med. Chem., 57 (11): 4720-44. [PMID:24819116]

12. Katayama R, Khan TM, Benes C, Lifshits E, Ebi H, Rivera VM, Shakespeare WC, Iafrate AJ, Engelman JA, Shaw AT. (2011) Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc. Natl. Acad. Sci. U.S.A., 108 (18): 7535-40. [PMID:21502504]

13. Kinoshita K, Asoh K, Furuichi N, Ito T, Kawada H, Hara S, Ohwada J, Miyagi T, Kobayashi T, Takanashi K et al.. (2012) Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). Bioorg. Med. Chem., 20 (3): 1271-80. [PMID:22225917]

14. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, Small D, Levis M. (2017) Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood, 129 (2): 257-260. [PMID:27908881]

15. Lewis RT, Bode CM, Choquette DM, Potashman M, Romero K, Stellwagen JC, Teffera Y, Moore E, Whittington DA, Chen H et al.. (2012) The discovery and optimization of a novel class of potent, selective, and orally bioavailable anaplastic lymphoma kinase (ALK) inhibitors with potential utility for the treatment of cancer. J. Med. Chem., 55 (14): 6523-40. [PMID:22734674]

16. Lovly CM, Heuckmann JM, de Stanchina E, Chen H, Thomas RK, Liang C, Pao W. (2011) Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res., 71 (14): 4920-31. [PMID:21613408]

17. Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M et al.. (2013) Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J. Med. Chem., 56 (14): 5675-90. [PMID:23742252]

18. Milkiewicz KL, Weinberg LR, Albom MS, Angeles TS, Cheng M, Ghose AK, Roemmele RC, Theroff JP, Underiner TL, Zificsak CA et al.. (2010) Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. Bioorg. Med. Chem., 18 (12): 4351-62. [PMID:20483621]

19. Ott GR, Cheng M, Learn KS, Wagner J, Gingrich DE, Lisko JG, Curry M, Mesaros EF, Ghose AK, Quail MR et al.. (2016) Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK). J. Med. Chem., 59 (16): 7478-96. [PMID:27527804]

20. Ott GR, Tripathy R, Cheng M, McHugh R, Anzalone AV, Underiner TL, Curry MA, Quail MR, Lu L, Wan W et al.. (2010) Discovery of a potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity. ACS Med Chem Lett, 1 (9): 493-8. [PMID:24900237]

21. Powell CE, Gao Y, Tan L, Donovan KA, Nowak RP, Loehr A, Bahcall M, Fischer ES, Jänne PA, George RE et al.. (2018) Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK). J. Med. Chem., 61 (9): 4249-4255. [PMID:29660984]

22. Sabbatini P, Korenchuk S, Rowand JL, Groy A, Liu Q, Leperi D, Atkins C, Dumble M, Yang J, Anderson K et al.. (2009) GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol. Cancer Ther., 8 (10): 2811-20. [PMID:19825801]

23. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

How to cite this page

Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family: ALK receptor tyrosine kinase. Last modified on 08/11/2019. Accessed on 19/11/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1839.