Drug Information

Drug (ID: DG01482) and It's Reported Resistant Information

• Name: NAV-2729
• Synonyms: NAV-2729; 419547-11-8; 2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; CHEMBL3716578; NAV 2729; 2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)-1H-pyrazolo[1,5-a]pyrimidin-7-one; 3-(4-Chlorophenyl)-5-(4-nitrophenyl)-2-(phenylmethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; NAV-2729Grassofermata; Oprea1_305395; SCHEMBL13516218; NAV2729; CHEBI:132811; AMY23749; EX-A2011; BDBM50168142; AKOS030211129; ZINC106616565; BS-16805; HY-112473; CS-0046101; D80454; 2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one
• Target: .; NOUNIPROTAC; [1]
• Formula: 4
• IsoSMILES: C1=CC=C(C=C1)CC2=C(C3=NC(=CC(=O)N3N2)C4=CC=C(C=C4)[N+](=O)[O-])C5=CC=C(C=C5)Cl
• InChI: InChI=1S/C25H17ClN4O3/c26-19-10-6-18(7-11-19)24-22(14-16-4-2-1-3-5-16)28-29-23(31)15-21(27-25(24)29)17-8-12-20(13-9-17)30(32)33/h1-13,15,28H,14H2
• InChIKey: WHYGBVWGARJOCS-UHFFFAOYSA-N
• PubChem CID: 2257249

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

Uveal melanoma [ICD-11: 2D0Y]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Guanine nucleotide-binding protein alpha-q (GNAQ) [1]

• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mel921 cells; N.A.; .; N.A.
• In Vitro Model: Mel202 cells; Eye; Homo sapiens (Human); CVCL_C301
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Mechanism Description: Activating mutations in Galphaq proteins, which form the a subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic Galphaq signaling to induce all of these downstream pathways as well as beta-catenin signaling. ARF6 activates these diverse pathways through a common mechanism-the trafficking of GNAQ and beta-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively. Blocking ARF6 with a small molecule reduces uveal melanoma cell proliferation and tumorigenesis in a mouse model, confirming the functional relevance of this pathway.

References

• Ref 1: ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal MelanomaCancer Cell. 2016 Jun 13;29(6):889-904. doi: 10.1016/j.ccell.2016.04.015. Epub 2016 Jun 2.