Drug Information

Drug (ID: DG01260) and It's Reported Resistant Information

• Name: YN-968D1
• Synonyms: Apatinib; Apatinib Mesylate; 1218779-75-9; Rivoceranib mesylate; YN968D1; YN-968D1; UNII-TK02X14ASJ; YN 968D1; TK02X14ASJ; N-(4-(1-Cyanocyclopentyl)phenyl)-2-((pyridin-4-ylmethyl)amino)nicotinamide Mesylate; 3-Pyridinecarboxamide, N-(4-(1-cyanocyclopentyl)phenyl)-2-((4-pyridinylmethyl)amino)-, methanesulfonate (1:1); N-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide;methanesulfonic acid; Apatinib mesylate; 3-Pyridinecarboxamide, N-[4-(1-cyanocyclopentyl)phenyl]-2-[(4-pyridinylmethyl)amino]-, methanesulfonate (1:1); Alitan (TN); Apatinib-YN968D1; Apatinib - YN968D1; Rivoceranib mesylate (USAN); MLS006011286; CHEMBL3545414; SCHEMBL21847695; DTXSID80153427; HMS3655H12; AOB87128; BCP15234; Apatinib (registered name in China); BDBM50152828; s2221; AKOS026750547; BCP9000308; CCG-269641; CS-0694; SB16589; N-(4-(1-cyanocyclopentyl)phenyl)-2-((pyridin-4-ylmethyl)amino)nicotinamide methanesulfonate; HY-13342; SMR004703036; SW220296-1; D11289; N-(4-(1-cyanocyclopentyl)phenyl)-2-(pyridin-4-ylmethylamino)nicotinamide mesylate; N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxyamide mesylate; N-(4-(1-cyanocyclopentyl)phenyl)-2-((pyridin-4-ylmethyl)amino)pyridine-3-carboxamide mesylate
• Indication:
  In total 1 Indication(s)
  Breast cancer [ICD-11: 2C60]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Thyroid cancer [ICD-11: 2D10]; [1]
• Target: Vascular endothelial growth factor receptor 2 (KDR); VGFR2_HUMAN; [1]
• Formula: C25H27N5O4S
• IsoSMILES: CS(=O)(=O)O.C1CCC(C1)(C#N)C2=CC=C(C=C2)NC(=O)C3=C(N=CC=C3)NCC4=CC=NC=C4
• InChI: 1S/C24H23N5O.CH4O3S/c25-17-24(11-1-2-12-24)19-5-7-20(8-6-19)29-23(30)21-4-3-13-27-22(21)28-16-18-9-14-26-15-10-18;1-5(2,3)4/h3-10,13-15H,1-2,11-12,16H2,(H,27,28)(H,29,30);1H3,(H,2,3,4)
• InChIKey: FYJROXRIVQPKRY-UHFFFAOYSA-N
• PubChem CID: 45139106
• TTD Drug ID: D0SZ6E
• VARIDT ID: DR00819

Type(s) of Resistant Mechanism of This Drug

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Thyroid cancer [ICD-11: 2D10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Forkhead box K2 (FOXK2) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGFA/VEGFR1 signaling pathway; Activation; hsa05205
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vitro Model: SH-1-V2 cells; Esophagus; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: On VEGFR2 blockage by specific targeting agent, such as Apatinib, FOXK2 could rapidly trigger therapeutic resistance. Mechanical analyses revealed that VEGFA transcriptionally induced by FOXK2 could bind to VEGFR1 as a compensation for VEGFR2 blockage, which promoted angiogenesis by activating ERK, PI3K/AKT and P38/MAPK signaling in human umbilical vein endothelial cells (HUVECs). Synergic effect on anti-angiogenesis could be observed when VEGFR1 suppressor AF321 was included in VEGFR2 inhibition system, which clarified the pivot role of FOXK2 in VEGFR2 targeting therapy resistance.

Key Molecule: Vascular endothelial growth factor A (VEGFA) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Anaplastic thyroid cancer [ICD-11: 2D10.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: VEGFA/VEGFR1 signaling pathway; Activation; hsa05205
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vitro Model: SH-1-V2 cells; Esophagus; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: On VEGFR2 blockage by specific targeting agent, such as Apatinib, FOXK2 could rapidly trigger therapeutic resistance. Mechanical analyses revealed that VEGFA transcriptionally induced by FOXK2 could bind to VEGFR1 as a compensation for VEGFR2 blockage, which promoted angiogenesis by activating ERK, PI3K/AKT and P38/MAPK signaling in human umbilical vein endothelial cells (HUVECs). Synergic effect on anti-angiogenesis could be observed when VEGFR1 suppressor AF321 was included in VEGFR2 inhibition system, which clarified the pivot role of FOXK2 in VEGFR2 targeting therapy resistance.

References

• Ref 1: FOXK2 transcriptionally activating VEGFA induces apatinib resistance in anaplastic thyroid cancer through VEGFA/VEGFR1 pathway .Oncogene. 2021 Oct;40(42):6115-6129. doi: 10.1038/s41388-021-01830-5. Epub 2021 Sep 6. 10.1038/s41388-021-01830-5