Drug Information

Drug (ID: DG00627) and It's Reported Resistant Information

• Name: SCH772984
• Synonyms: SCH772984; 942183-80-4; SCH-772984; (R)-1-(2-oxo-2-(4-(4-(pyrimidin-2-yl)phenyl)piperazin-1-yl)ethyl)-N-(3-(pyridin-4-yl)-1H-indazol-5-yl)pyrrolidine-3-carboxamide; SCH 772984; CHEMBL3590107; (3R)-1-[2-Oxo-2-[4-[4-(2-pyrimidinyl)phenyl]-1-piperazinyl]ethyl]-N-[3-(4-pyridinyl)-1H-indazol-5-yl]-3-pyrrolidinecarboxamide; (3~{R})-1-[2-oxidanylidene-2-[4-(4-pyrimidin-2-ylphenyl)piperazin-1-yl]ethyl]-~{N}-(3-pyridin-4-yl-1~{H}-indazol-5-yl)pyrrolidine-3-carboxamide; (3r)-1-(2-Oxo-2-{4-[4-(Pyrimidin-2-Yl)phenyl]piperazin-1-Yl}ethyl)-N-[3-(Pyridin-4-Yl)-2h-Indazol-5-Yl]pyrrolidine-3-Carboxamide; (3R)-1-[2-oxo-2-[4-(4-pyrimidin-2-ylphenyl)piperazin-1-yl]ethyl]-N-(3-pyridin-4-yl-1H-indazol-5-yl)pyrrolidine-3-carboxamide; 38Z; GTPL8056; SCHEMBL12151489; AOB6425; EX-A296; CHEBI:167670; C33H33N9O2; 2711AH; BDBM50094464; MFCD11878503; NSC775636; s7101; ZINC96174209; AKOS025402018; CS-1421; NSC-775636; SCH772984, SCH 984; NCGC00350780-05; NCGC00350780-10; NCGC00350780-11; (R)-1-(2-oxo-2-(4-(4-(pyrimidin-2-yl)phenyl)piperazin-1-yl)ethyl)-N-(3-(pyridin-4-yl)-1H-indazol-5-y; (R)-1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid (3-pyridin-4-yl-1H-indazol-5-yl)-amide; AC-28198; CID 24866313; HY-50846; QC-11359; F31041; A859514; Q27088760; (3R)-1-(2-OXO-2-{4-[4-(PYRIMIDIN-2-YL)PHENYL]PIPERAZIN-1-YL}ETHYL)-N-[3-(PYRIDIN-4-YL)-1H-INDAZOL-5-YL]PYRROLIDINE-3-CARBOXAMIDE; (R)-1-(2-oxo-2-(4-(4-(pyrimidin-2-yl)phenyl)piperazin-1-yl)ethyl)-N-(3-(pyridin-4-yl)-1H-indazol-5-; F3Z
• Indication:
  In total 1 Indication(s)
  Discovery agent [ICD-11: N.A.]; Investigative; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Unclassified pleomorphic sarcoma [ICD-11: 2B54]; [1]
• Target: Extracellular signal-regulated kinase 2 (ERK2); MK01_HUMAN; [1]
• Formula: C33H33N9O2
• IsoSMILES: C1CN(C[C@@H]1C(=O)NC2=CC3=C(C=C2)NN=C3C4=CC=NC=C4)CC(=O)N5CCN(CC5)C6=CC=C(C=C6)C7=NC=CC=N7
• InChI: 1S/C33H33N9O2/c43-30(42-18-16-41(17-19-42)27-5-2-24(3-6-27)32-35-11-1-12-36-32)22-40-15-10-25(21-40)33(44)37-26-4-7-29-28(20-26)31(39-38-29)23-8-13-34-14-9-23/h1-9,11-14,20,25H,10,15-19,21-22H2,(H,37,44)(H,38,39)/t25-/m1/s1
• InChIKey: HDAJDNHIBCDLQF-RUZDIDTESA-N
• PubChem CID: 24866313
• TTD Drug ID: D08XVZ

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

Unclassified pleomorphic sarcoma [ICD-11: 2B54]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase HRas (HRAS) [1]

• Resistant Disease: Unclassified pleomorphic sarcoma [ICD-11: 2B54.0]
• Molecule Alteration: Missense mutation; p.G12V
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.98 Å; PDB: 7SCW
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.96 Å; PDB: 7SCX

RMSD: 0.47; TM score: 0.99104; Amino acid change: G12V

• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: RAS signaling pathway; Activation; hsa04014
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); CVCL_0594
• In Vivo Model: SCID/Beige mice model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Hras G12V mutation changed the drug target,impairing the ability to inhibit RAS-RAF-MEK-ERK signaling.

Colorectal cancer [ICD-11: 2B91]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 luminogenic assay

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vivo Model: Female athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 luminogenic assay

References

• Ref 1: Sensitivity and Resistance of Oncogenic RAS-Driven Tumors to Dual MEK and ERK Inhibition .Cancers (Basel). 2021 Apr 13;13(8):1852. doi: 10.3390/cancers13081852. 10.3390/cancers13081852
• Ref 2: Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway OncogenesCancer Cell. 2015 Aug 10;28(2):170-82. doi: 10.1016/j.ccell.2015.07.001.