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Details

Stereochemistry ABSOLUTE
Molecular Formula C24H31N3O3.C3H6O3
Molecular Weight 499.5992
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ONALESPIB LACTATE

SMILES

C[C@H](O)C(O)=O.CC(C)C1=CC(C(=O)N2CC3=C(C2)C=C(CN4CCN(C)CC4)C=C3)=C(O)C=C1O

InChI

InChIKey=VYRWEWHOAMGLLW-WNQIDUERSA-N
InChI=1S/C24H31N3O3.C3H6O3/c1-16(2)20-11-21(23(29)12-22(20)28)24(30)27-14-18-5-4-17(10-19(18)15-27)13-26-8-6-25(3)7-9-26;1-2(4)3(5)6/h4-5,10-12,16,28-29H,6-9,13-15H2,1-3H3;2,4H,1H3,(H,5,6)/t;2-/m.0/s1

HIDE SMILES / InChI

Description

Onalespib (AT13387; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl] methanone, l-lactic acid salt), is wholly owned by Astex, a novel, high-affinity HSP90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. As a targeted inhibitor of Hsp90, onalespib has the potential to control the proliferation of multiple solid tumors and hematological malignancies where uncontrolled cell growth is dependent on the interaction between Hsp90 and its client proteins. Astex is pursuing an approach based on the observation that addition of onalespib to a molecularly targeted agent may delay the emergence of resistance to the agent, and hence prolong the window of therapeutic benefit. Onalespib is currently being evaluated via a CRADA with the National Cancer Institute (NCI) in various tumor types, and in a Phase 1/2 clinical study in combination with AT7519, Astex CDK inhibitor.

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
0.7 nM [Kd]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown
Primary
Unknown

Cmax

ValueDoseCo-administeredAnalytePopulation
3790 ng/mL
310 mg/m² 1 times / week multiple, intravenous
ONALESPIB plasma
Homo sapiens
923 ng/mL
180 mg/m² single, intravenous
ONALESPIB plasma
Homo sapiens
1790 ng/mL
260 mg/m² 1 times / week multiple, intravenous
ONALESPIB plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
7293 ng × h/mL
310 mg/m² 1 times / week multiple, intravenous
ONALESPIB plasma
Homo sapiens
2376 ng × h/mL
180 mg/m² single, intravenous
ONALESPIB plasma
Homo sapiens
4905 ng × h/mL
260 mg/m² 1 times / week multiple, intravenous
ONALESPIB plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
7 h
310 mg/m² 1 times / week multiple, intravenous
ONALESPIB plasma
Homo sapiens
7 h
180 mg/m² single, intravenous
ONALESPIB plasma
Homo sapiens
6.6 h
260 mg/m² 1 times / week multiple, intravenous
ONALESPIB plasma
Homo sapiens

Funbound

ValueDoseCo-administeredAnalytePopulation
16.3%
unknown
ONALESPIB plasma
Homo sapiens

PubMed

Sample Use Guides

In Vivo Use Guide
At 13387 (ONALESPIB) administered as a 1-hr IV infusion at a starting dose of 120 mg/m2 on Day 1 and Day 2 weekly for 3 weeks in a 4-week cycle.
Route of Administration: Intravenous
In Vitro Use Guide
AT13387 (50 nM) ONALESPIB treatment resulted in G2/M-phase arrest and significantly reduced the migration capacity. The expression of selected proteins involved in DNA repair, cell-signaling and cell growth was downregulated in vitro, though the expression of most investigated proteins recurred after 8-24 h. AT13387 induces effective cytotoxic activity in all cancer cell lines (A431, HCT116, LS174T and H314) with an IC50 < 20 nM.