XL-888

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C29H37N5O3
Molecular Weight	503.6358
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC[C@@H](C)NC1=CC(C(=O)N[C@@H]2C[C@@H]3CC[C@H](C2)N3C4=NC=C(C=C4)C(=O)C5CC5)=C(C)C=C1C(N)=O

InChI

InChIKey=LHGWWAFKVCIILM-HLRQEUIKSA-N

InChI=1S/C29H37N5O3/c1-4-17(3)32-25-14-23(16(2)11-24(25)28(30)36)29(37)33-20-12-21-8-9-22(13-20)34(21)26-10-7-19(15-31-26)27(35)18-5-6-18/h7,10-11,14-15,17-18,20-22,32H,4-6,8-9,12-13H2,1-3H3,(H2,30,36)(H,33,37)/t17-,20-,21+,22-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C29H37N5O3
Molecular Weight	503.6358
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	4 / 4
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.exelixis.com/pipeline/xl888 | https://www.ncbi.nlm.nih.gov/pubmed/22877636
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/22351686

XL-888 is a highly potent and orally bioavailable ATP-competitive inhibitor of HSP90, a molecular chaperone protein that regulates the activity and stability of a range of key regulatory proteins, including a number of kinases implicated in cancer cell growth and survival. In preclinical studies, XL-888 has been shown to inhibit the proliferation of a broad panel of human tumor cell lines, and to induce marked degradation of HSP90 client proteins, including BRAF, MET, and HER2. XL-888 was discovered by Exelixis and is wholly owned by the company. XL-888 is currently in Phase I clinical trials for the treatment of malignant melanoma.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Heat shock protein HSP90 35 Target ID: CHEMBL2095165 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22877636	Inhibitor 8504		24.0 nM [IC50]
SK-MEL-28 1 Target ID: CHEMBL614919 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22877636	Inhibitor 8504		0.3 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Melanoma 88 Sources: https://clinicaltrials.gov/ct2/show/NCT01657591	Primary		Phase I 438	Unknown Approved Use Unknown

AUC

Value	Dose	Co-administered	Analyte	Population
11.15 μM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22877636	5 mg/kg single, intravenous dose: 5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		XL-888 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
1.4 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22877636	5 mg/kg single, intravenous dose: 5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		XL-888 plasma	Mus musculus population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252	inhibitor 2438	inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1741

Drug as perpetrator

Target	Modality	Activity
CYP2D6 2546	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=404904729	no
P-gp 1932	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363680173	yes [IC50 0.13 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=404904729	yes [IC50 3.7908 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=404904729	yes [IC50 8.4866 uM]

PubMed

Title	Date	PubMed
Evaluating melanoma drug response and therapeutic escape with quantitative proteomics.	2014-07	24760959
Inhibition of Wee1, AKT, and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS-mutant melanoma.	2013-06	23538902
The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms.	2012-05-01	22351686

Patents

Sample Use Guides

In Vivo Use Guide

XL-888 30 mg by mouth (PO) twice weekly (BIW). Level 2: XL888 45 mg PO BIW. Level 3: XL-888 60 mg PO BIW. Level 3: XL-888 90 mg PO BIW.

Route of Administration: Oral

In Vitro Use Guide

Treatment of the vemurafenib resistant human melanoma cell lines with XL-888 (300 nM) induced high levels (>66%) of apoptosis as shown by Annexin-V binding, caspase-3 cleavage and loss of mitochondrial membrane potential (TMRM) in every cell line tested

Substance Class	Chemical Created by `admin` on `Mon Mar 31 20:55:58 GMT 2025` Edited by `admin` on `Mon Mar 31 20:55:58 GMT 2025`
Record UNII	7M346920EV
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

XL-888

Common Name

English

1,4-BENZENEDICARBOXAMIDE, N1-((3-ENDO)-8-(5-(CYCLOPROPYLCARBONYL)-2-PYRIDINYL)-8-AZABICYCLO(3.2.1)OCT-3-YL)-2-METHYL-5-(((1R)-1-METHYLPROPYL)AMINO)-

Preferred Name

English

5-((R)-SEC-BUTYLAMINO)-N1-((1R,3S,5S)-8-(5-(CYCLOPROPANECARBONYL)PYRIDIN-2-YL)-8-AZABICYCLO(3.2.1)OCTAN-3-YL)-2-METHYLTEREPHTHALAMIDE

Common Name

English

EXEL-4888

Common Name

English

XL888

Common Name

English

Code System Code Type Description

FDA UNII

7M346920EV