XL-019

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H28N6O2
Molecular Weight	444.5288
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O=C(NC1=CC=C(C=C1)C2=NC(NC3=CC=C(C=C3)N4CCOCC4)=NC=C2)[C@@H]5CCCN5

InChI

InChIKey=ISOCDPQFIXDIMS-QHCPKHFHSA-N

InChI=1S/C25H28N6O2/c32-24(23-2-1-12-26-23)28-19-5-3-18(4-6-19)22-11-13-27-25(30-22)29-20-7-9-21(10-8-20)31-14-16-33-17-15-31/h3-11,13,23,26H,1-2,12,14-17H2,(H,28,32)(H,27,29,30)/t23-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24374145http://www.bionity.com/en/news/64926/exelixis-files-ind-application-for-xl019-a-novel-anticancer-compound-targeting-the-jak-stat-signaling-pathway.html
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/23127890

XL-019 is a potent inhibitor of JAK2 (IC50 = 2 nM), and is selective for JAK2 versus the other members of the JAK kinase family (JAK1 IC50 = 130 nM, JAK3 IC50 = 250 nM, TYK2 IC50 = 340 nM). It is active against both wild type and mutationally activated forms of JAK2, and showed good oral bioavailability and pharmacodynamic properties in preclinical studies. Activating mutations in JAK2 are frequently observed in patients with myeloproliferative disorders such as myelofibrosis, polycythemia vera and essential thrombocythemia. JAK2 activity is also upregulated via multiple mechanisms in many lymphomas and solid tumors. XL-019 was being developed by Exelixis for the treatment of myelofibrosis and polycythaemia vera.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tyrosine-protein kinase JAK2 55 Target ID: CHEMBL2971 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23127890 \| http://www.bionity.com/en/news/64926/exelixis-files-ind-application-for-xl019-a-novel-anticancer-compound-targeting-the-jak-stat-signaling-pathway.html	Inhibitor 8297		2.2 nM [IC50]
Tyrosine-protein kinase JAK2 55 Target ID: CHEMBL2971 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23127890	Inhibitor 8297		2.2 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Polycythemia vera 15 Sources: https://clinicaltrials.gov/ct2/show/NCT00595829 http://adisinsight.springer.com/drugs/800027348 https://www.ncbi.nlm.nih.gov/pubmed/23610611	Primary	Phase I 428	Unknown Approved Use Unknown
Myelofibrosis 15 Sources: https://clinicaltrials.gov/ct2/show/NCT00522574 http://adisinsight.springer.com/drugs/800027348 https://www.ncbi.nlm.nih.gov/pubmed/23610611	Primary	Phase I 428	Unknown Approved Use Unknown
Polycythemia vera 15 Sources: https://clinicaltrials.gov/ct2/show/NCT00595829	Primary	Phase I 428	Unknown Approved Use Unknown
Myelofibrosis 15 Sources: https://clinicaltrials.gov/ct2/show/NCT00522574	Primary	Phase I 428	Unknown Approved Use Unknown
Thrombocythemia 4 Sources: https://clinicaltrials.gov/ct2/show/NCT00522574	Primary	Phase I 428	Unknown Approved Use Unknown

T_1/2

Value	Dose	Co-administered	Analyte	Population
21 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24374145/	300 mg 1 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		XL-019 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461

Drug as perpetrator

Target	Modality	Activity
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=363680792	inconclusive [IC50 23.9185 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363680792	no
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29187454/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363680792	yes [IC50 14.581 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=363680792	yes [IC50 2.1317 uM]

PubMed

Title	Date	PubMed
SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.	2012 Dec 15	23127890

Patents

Sample Use Guides

In Vivo Use Guide

21 patients were treated in 28-day cycles with XL019 in subsequent order: 25 mg continuously daily (n = 8), 25 mg Monday/Wednesday/Friday (25 mg TIW, n = 8), and 50 mg continuously daily (n = 5).

Route of Administration: Oral

In Vitro Use Guide

XL019 activity was evaluated in HEL 92.1.7 cells as STAT1 (IC50=386.4nM) and STAT3 (IC50=695nM) phosphorylation.

Name

Type

Language

XL-019

Common Name

English

2-PYRROLIDINECARBOXAMIDE, N-(4-(2-((4-(4-MORPHOLINYL)PHENYL)AMINO)-4-PYRIMIDINYL)PHENYL)-, (2S)-

Systematic Name

English

XL019

Code

English

Code System Code Type Description

NCI_THESAURUS

C90573