Drug Information

Drug (ID: DG02007) and It's Reported Resistant Information

• Name: Alisertib
• Synonyms: Alisertib|1028486-01-2|MLN8237|MLN-8237|MLN 8237|4-((9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)amino)-2-methoxybenzoic acid|MLN8237 (Alisertib)|Alisertib [USAN]|4-[[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid|Alisertib [USAN:INN]|Alisertib (USAN)|T66ES73M18|ALISERTIB [INN]|ALISERTIB [WHO-DD]|CHEMBL483158|DTXSID30145539|MLN 8237 (Contain 10% DMSO)|4-((9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-yl)amino)-2-methoxybenzoic acid|Benzoic acid, 4-((9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido(5,4-d)(2)benzazepin-2-yl)amino)-2-methoxy-|4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid|alisertibum|UNII-T66ES73M18|4-((13-chloro-10-(2-fluoro-6-methoxyphenyl)-3,5,9-triazatricyclo(9.4.0.0^(2,7))pentadeca-1(15),2,4,6,9,11,13-heptaen-4-yl)amino)-2-methoxybenzoic acid|4-((9-CHLORO-7-(2-FLUORO-6-METHOXYPHENYL)-5H-PYRIMIDO(5,4-D)(2)BENZAZEPIN-2-YL)AMINO)-2-METHOXY-BENZOIC ACID|4-((9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido(5,4-d)(2)benzazepin-2-yl)amino)-2-methoxybenzoic acid|4-{[13-chloro-10-(2-fluoro-6-methoxyphenyl)-3,5,9-triazatricyclo[9.4.0.0^{2,7}]pentadeca-1(15),2,4,6,9,11,13-heptaen-4-yl]amino}-2-methoxybenzoic acid|4-{[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxy-benzoic acid|Benzoic acid, 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxy-; 4-[[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid; MLN 8237|MFCD16621243|MLN8237,Alisertib|Kinome_3770|Alisertib; MLN8237|Alisertib (MLN8237)|MLN8237 (Alisertib)?|MLS006011041|SCHEMBL855823|GTPL7790|DTXCID4068030|EX-A024|CHEBI:125628|ZLHFILGSQDJULK-UHFFFAOYSA-N|HMS3654E08|HMS3673I07|HMS3743E17|BCP01823|Aurora A Kinase Inhibitor MLN8237|BDBM50277545|NSC759677|NSC799329|s1133|AKOS015924647|BCP9000956|CCG-264832|CS-0106|DB05220|FM16476|NSC-759677|NSC-799329|SB16658|SDCCGSBI-0646927.P001|NCGC00263271-01|NCGC00263271-02|NCGC00263271-10|4-(9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-2-methoxybenzoic acid|AC-25236|AS-17005|HY-10971|SMR004702834|NS00072479|SW219771-1|D10085|EN300-6482023|BRD-K75295174-001-03-5|BRD-K75295174-001-05-0|Q15633917|Z2037281068|4-(9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[e]pyrimido[5,4-c]azepin-2-ylamino)-2-methoxybenzoic acid|4-[[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxy-benzoic acid;Alisertib|4-{[13-chloro-10-(2-fluoro-6-methoxyphenyl)-3,5,9-triazatricyclo[9.4.0.0,2,7]pentadeca-1(11),2(7),3,5,9,12,14-heptaen-4-yl]amino}-2-methoxybenzoic acid|4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl) -5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid|A5B
• Indication:
  In total 1 Indication(s)
  Small-cell lung cancer [ICD-11: 2C25]; Phase 2
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Brain cancer [ICD-11: 2A00]; [1]
  Colorectal cancer [ICD-11: 2B91]; [2]
• Target: Aurora kinase A (AURKA); AURKA_HUMAN
• Formula: C27H20ClFN4O4
• IsoSMILES: COC1=C(C(=CC=C1)F)C2=NCC3=CN=C(N=C3C4=C2C=C(C=C4)Cl)NC5=CC(=C(C=C5)C(=O)O)OC
• InChI: InChI=1S/C27H20ClFN4O4/c1-36-21-5-3-4-20(29)23(21)25-19-10-15(28)6-8-17(19)24-14(12-30-25)13-31-27(33-24)32-16-7-9-18(26(34)35)22(11-16)37-2/h3-11,13H,12H2,1-2H3,(H,34,35)(H,31,32,33)
• InChIKey: ZLHFILGSQDJULK-UHFFFAOYSA-N
• PubChem CID: 24771867
• ChEBI ID: CHEBI:125628
• TTD Drug ID: D0S4JK

Type(s) of Resistant Mechanism of This Drug

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Aurora kinase A (AURKA) [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Autophosphorylation; Thr288
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: GBM22 PDX cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: SF188 PDX cells; Brain; Homo sapiens (Human); CVCL_6948
• In Vitro Model: Silenced PGC1alpha in GBM22 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: Silenced PGC1alpha in SF188 cells; Brain; Homo sapiens (Human); CVCL_6948
• In Vitro Model: Transfect T58A mutant c-Myc in GBM22 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: Transfected c-Myc in GBM22 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The response to Aurora kinase A inhibitors depends on glycolysis and that tumor cells with an oxidative metabolic phenotype will be more resistant to Aurora kinase A inhibitor treatment. Moreover, in a manner dependent on the transcription factors c-MYC and PGC1alpha treatment with Aurora kinase A inhibitors renders GBM cells highly oxidative and dependent on fatty acid oxidation that in turn mediates them to be susceptible to inhibitors of FAO in vitro and in vivo.

Key Molecule: Aurora kinase A (AURKA) [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Autophosphorylation; Thr288
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: GBM22 orthotopic PDX model; orthotopic murine GBM model; subcutis of immunocompromised Nu/Nu mice, GBM12 cells; subcutis of immunocompromised Nu/Nu mice, GBM43 cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: The response to Aurora kinase A inhibitors depends on glycolysis and that tumor cells with an oxidative metabolic phenotype will be more resistant to Aurora kinase A inhibitor treatment. Moreover, in a manner dependent on the transcription factors c-MYC and PGC1alpha treatment with Aurora kinase A inhibitors renders GBM cells highly oxidative and dependent on fatty acid oxidation that in turn mediates them to be susceptible to inhibitors of FAO in vitro and in vivo.

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: microRNA-125b (miR-125b) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell colony formation assay
• Mechanism Description: Similarly, miR-125b mimic decreased the glycolysis [(25.28±9.51) mpH/min] in HCT-8-7T cells as compared with that [(54.38±12.70)mpH/min,P=0.003] in HCT-8-7T cells transfected with control. Meanwhile, in comparison with control transfected HCT-8-7T cells, miR-125b mimic also significantly led to an increase in the levels of p53 and beta-catenin, in parallel with a decrease in the levels of PFK1 and HK1 in HCT-8-7T cells

References

• Ref 1: Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma. Nat Commun. 2021 Sep 1;12(1):5203.
• Ref 2: [Targeting microRNA-125b inhibited the metastasis of Alisertib resistance cells through mediating p53 pathway]. Zhonghua Zhong Liu Za Zhi. 2023 Jun 23;45(6):499-507.