HSP-990

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C20H18FN5O2
Molecular Weight	379.3876
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC=CC(=N1)C2=CC(F)=CC=C2[C@H]3CC4=NC(N)=NC(C)=C4C(=O)N3

InChI

InChIKey=WSMQUUGTQYPVPD-OAHLLOKOSA-N

InChI=1S/C20H18FN5O2/c1-10-18-16(26-20(22)23-10)9-15(25-19(18)27)12-7-6-11(21)8-13(12)14-4-3-5-17(24-14)28-2/h3-8,15H,9H2,1-2H3,(H,25,27)(H2,22,23,26)/t15-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22246440
Curator's Comment: Description was created based on several sources, including https://www.scbt.com/scbt/product/hsp-990-934343-74-5

HSP-990 is an oral Hsp90 inhibitor being developed by Novartis in a collaboration with Vernalis. It is also known by NVP-HSP990. HSP-990 is an inhibitor of human heat-shock protein 90 (Hsp90) with potential antineoplastic activity. Hsp-990 binds to and inhibits the activity of Hsp90, which may result in the proteasomal degradation of oncogenic client proteins, including HER2/ERBB2, and the inhibition of tumor cell proliferation. Hsp90, upregulated in a variety of tumor cells, is a molecular chaperone that plays a key role in the conformational maturation, stability and function of oncogenic signaling proteins, such as HER2/ERBB2, AKT, RAF1, BCR-ABL, and mutated p53, as well as many other molecules that are important in cell cycle regulation and/or immune responses.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Heat shock protein HSP 90-alpha 11 Target ID: CHEMBL3880 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22246440	Inhibitor 8297	0.6 nM [IC50]
Heat shock protein HSP 90-beta 13 Target ID: CHEMBL4303 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22246440	Inhibitor 8297	0.8 nM [IC50]
Heat shock protein HSP 90-alpha 11 Target ID: CHEMBL3880 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25368984	Inhibitor 8297	13.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Advanced solid cancer 28 Sources: https://clinicaltrials.gov/ct2/show/NCT00879905	Primary		Phase I 428	Unknown Approved Use Unknown
Advanced solid cancer 28 Sources: https://clinicaltrials.gov/ct2/show/NCT00879905	Primary		Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
496 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25625276	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		HSP-990 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
700 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25625276	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:		HSP-990 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
10108 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25625276	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		HSP-990 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
9712 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25625276	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:		HSP-990 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
20.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25625276	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		HSP-990 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
17.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25625276	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:		HSP-990 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as perpetrator

Target	Modality	Activity
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=404904725	inconclusive [IC50 37.9083 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=404904725	yes [IC50 10.684 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=404904725	yes [IC50 6.7412 uM]

PubMed

Title	Date	PubMed
The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo.	2012 Mar	22246440
The novel, orally bioavailable HSP90 inhibitor NVP-HSP990 induces cell cycle arrest and apoptosis in multiple myeloma cells and acts synergistically with melphalan by increased cleavage of caspases.	2012 May	22309072
Design, structure-activity relationship, and in vivo characterization of the development candidate NVP-HSP990.	2014 Nov 13	25368984

Patents

Sample Use Guides

In Vivo Use Guide

Heat-shock protein 990 was administered orally once or two times weekly on a flat dosing scale and treatment cycles were of 28 days duration. Heatshock protein 990 was supplied as 1, 2.5, 20 and 50mg hard gelatin capsules. Fasting conditions were required (study drug was taken 30 min after a light breakfast, followed by a 3-h fasting period). The twice-weekly dosing schedule required at least 72 h between the two doses, with both doses taken within a 7-day period. Administration of HSP990 was allowed until disease progression, unacceptable toxicity, investigator’s decision or patient withdrawal of consent.

Route of Administration: Oral

In Vitro Use Guide

GTL-16 Cells (1x103) were plated into 96 well tissue culture plates and cultured at 37 C, 5% CO2. Serially diluted HSP990 (up to 1 mkM) were added to the cells and were incubated for 72 hrs. at 37 C, 5% CO2. Cell proliferation was determined using Promega's CellTiter-Glo® Luminescent Cell Viability assay.

Name

Type

Language

HSP-990

Common Name

English

(R)-2-AMINO-7-(4-FLUORO-2-(6-METHOXYPYRIDIN-2-YL)PHENYL)-4-METHYL-7,8-DIHYDRO-6H-PYRIDO(4,3-D)PYRIMIDIN-5-ONE

Systematic Name

English

NVP-HSP990

Code

English

HSP 990 [WHO-DD]

Common Name

English

Code System Code Type Description

CAS

934343-74-5