Denfivontinib

Details

Stereochemistry	ACHIRAL
Molecular Formula	C25H25BrN6O2
Molecular Weight	521.409
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1CCC(CC1)NC2=NC(NC3=CC=C(OC4=CC=CC=C4)C=C3)=C5C(=O)NC=C(Br)C5=N2

InChI

InChIKey=SXWMIXPJPNCXQQ-UHFFFAOYSA-N

InChI=1S/C25H25BrN6O2/c1-32-13-11-17(12-14-32)29-25-30-22-20(26)15-27-24(33)21(22)23(31-25)28-16-7-9-19(10-8-16)34-18-5-3-2-4-6-18/h2-10,15,17H,11-14H2,1H3,(H,27,33)(H2,28,29,30,31)

HIDE SMILES / InChI

Molecular Formula	C25H25BrN6O2
Molecular Weight	521.409
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24532805

G749 is a Fms-like tyrosine receptor kinase 3 (FLT3) inhibitor and a promising next-generation drug candidate for the treatment of relapsed and refractory acute myeloid leukemia (AML) patients with various FLT3-ITD/FLT3-TKD mutants that shows the ability to overcome drug resistance. It demonstrated potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. It also displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G749 yielded complete tumor regression and increased life span in animal models.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Receptor-type tyrosine-protein kinase FLT3 4 Target ID: P36888 Gene ID: 2322.0 Gene Symbol: FLT3 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/24532805	Inhibitor 8297		0.4 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute myeloid leukemia 136 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24532805	Primary		Basic research	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia.	2014 Apr 3	24532805

Patents

Sample Use Guides

In Vivo Use Guide

To examine its antitumor efficacy, G749 HCl salt was administered orally every day for 28 days to the MV4-11 xenograft mice.

Route of Administration: Oral

In Vitro Use Guide

The antiproliferative activity of G749 was assessed in several leukemia cell lines. Five human leukemia cell lines seeded at a density of 2 × 10(4) cells per well were incubated with increasing concentrations of G749 (0.32, 1.6, 8, 40, 200, 1000, 5000 nM) for 72 hours at 37°C. G749 showed strong antiproliferation of leukemia cells addicted to FLT3-ITD (MV4-11 and Molm-14) in a dose-dependent manner, whereas it did not potently inhibit proliferation of leukemia cells without FLT3 expression (HEL and K562) or of non–FLT3-addicted cells with FLT3-WT (RS4-11).

Substance Class	Chemical Created by `admin` on `Sat Dec 16 12:50:41 GMT 2023` Edited by `admin` on `Sat Dec 16 12:50:41 GMT 2023`
Record UNII	B06W426B66
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

Denfivontinib

Official Name

English

Pyrido[4,3-d]pyrimidin-5(6H)-one, 8-bromo-2-[(1-methyl-4-piperidinyl)amino]-4-[(4-phenoxyphenyl)amino]-

Systematic Name

English

G-749

Code

English

38-bromo-11-methyl-6-oxa-2,4-diaza-3(2,4)-pyrido[4,3-d]pyrimidina-1(4)-piperidina-5(1,4),7(1)-dibenzenaheptaphan-35(36H)-one

Systematic Name

English

8-Bromo-2-[(1-methyl-4-piperidinyl)amino]-4-[(4-phenoxyphenyl)amino]pyrido[4,3-d]pyrimidin-5(6H)-one

Systematic Name

English

Denfivontinib [INN]

Common Name

English

Code System Code Type Description

FDA UNII

B06W426B66