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Details

Stereochemistry ACHIRAL
Molecular Formula C23H21N5O3S.ClH
Molecular Weight 483.97
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of AMUVATINIB HYDROCHLORIDE

SMILES

Cl.S=C(NCC1=CC2=C(OCO2)C=C1)N3CCN(CC3)C4=NC=NC5=C4OC6=C5C=CC=C6

InChI

InChIKey=IKQFRXPMBGQJGE-UHFFFAOYSA-N
InChI=1S/C23H21N5O3S.ClH/c32-23(24-12-15-5-6-18-19(11-15)30-14-29-18)28-9-7-27(8-10-28)22-21-20(25-13-26-22)16-3-1-2-4-17(16)31-21;/h1-6,11,13H,7-10,12,14H2,(H,24,32);1H

HIDE SMILES / InChI

Description

Amuvatinib (formerly known as MP470) is an oral multi-targeted tyrosine kinase inhibitor, which play critical roles in transducing growth signals to cancer cells. It suppresses c-MET, c-RET and the mutant forms of cKIT, PDGFR and FLT3. It also disrupts DNA repair likely through suppression of homologous recombination protein Rad51, an important survival pathway in many human cancers. In vitro and in vivo data have demonstrated amuvatinib synergy with DNA damaging agents including etoposide and doxorubicin. Overall, in the amuvatinib clinical development program, over 200 subjects were exposed to at least one dose of amuvatinib. In the Phase 1b clinical study in combination with carboplatin and etoposide, responses in small cell lung cancer (SCLC), neuroendocrine as well as other tumor types were observed. Human pharmacokinetic data suggest that co-administration of amuvatinib did not alter exposures of standard of care agents including carboplatin, etoposide, doxorubicin, paclitaxel, topotecan or erlotinib as measured by overall exposure. In the first-in-human study, durable clinical benefit was observed in the gastrointestinal stromal tumors (GIST) with modulation of Rad51 observed in skin punch biopsies. In clinical trials, amuvatinib has demonstrated a wide therapeutic window and shows minimal toxicity in the expected therapeutic dose range, despite suppressing several signaling pathways within cells. However, in spite of this, this drug was discontinued, because it was not pre-specified primary endpoints in the clinical proof of concept (cPOC) stage. But the combination of MP470 and Erlotinib, which target the HER family/PI3K/Akt pathway may represent a novel therapeutic strategy for prostate cancer.

CNS Activity

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown
Primary
Unknown
Primary
Unknown

Cmax

ValueDoseCo-administeredAnalytePopulation
644 ng/mL
360 mg 3 times / day multiple, oral
AMONAFIDE plasma
Homo sapiens
29.5 ng/mL
500 mg single, oral
AMONAFIDE plasma
Homo sapiens
81.7 ng/mL
500 mg 3 times / day multiple, oral
AMONAFIDE plasma
Homo sapiens
174 ng/mL
700 mg single, oral
AMONAFIDE plasma
Homo sapiens
61.5 ng/mL
700 mg single, oral
AMONAFIDE plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
2321 ng × h/mL
360 mg 3 times / day multiple, oral
AMONAFIDE plasma
Homo sapiens
129 ng × h/mL
500 mg single, oral
AMONAFIDE plasma
Homo sapiens
534 ng × h/mL
500 mg 3 times / day multiple, oral
AMONAFIDE plasma
Homo sapiens
1472 ng × h/mL
700 mg single, oral
AMONAFIDE plasma
Homo sapiens
674 ng × h/mL
700 mg single, oral
AMONAFIDE plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
11.7 h
360 mg 3 times / day multiple, oral
AMONAFIDE plasma
Homo sapiens
8.31 h
700 mg single, oral
AMONAFIDE plasma
Homo sapiens
11.6 h
700 mg single, oral
AMONAFIDE plasma
Homo sapiens

Funbound

ValueDoseCo-administeredAnalytePopulation
5%
unknown, unknown
AMUVATINIB serum
Homo sapiens

Doses

OverviewOther

Other InhibitorOther SubstrateOther Inducer



Drug as perpetrator​

Drug as victim

PubMed

Sample Use Guides

In Vivo Use Guide
Amuvatinib 300 mg three times a day + standard-of-care platinum-etoposide
Route of Administration: Oral
In Vitro Use Guide
MP470 was evaluated on prostate cancer cell lines (LNCaP, PC-3 and DU-145). Cells were exposed to differing doses of MP470 (1 to 10 μM) for 24 h. The drug was effective on LNCaP and PC-3 cells with an IC50 of ~4 μM and 8 μM, respectively. However, MP470 had only a modest effect on the viability of DU-145 cells. Cell cycle progression analyzed by flow cytometry showed that MP470 induced G1 arrest in A549 and LNCaP cells as they cannot be synchronized in G2/M by nocodazole compared to DMSO control. However, MP470 did not induce G1 arrest in PC-3 cells, implicating that this arrest is cell line specific.