Details
Stereochemistry | ACHIRAL |
Molecular Formula | C23H21N5O3S |
Molecular Weight | 447.51 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
S=C(NCC1=CC2=C(OCO2)C=C1)N3CCN(CC3)C4=NC=NC5=C4OC6=C5C=CC=C6
InChI
InChIKey=FOFDIMHVKGYHRU-UHFFFAOYSA-N
InChI=1S/C23H21N5O3S/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)
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/21903282Curator's Comment: description was created based on several sources, including
http://www.astx.com/content/resources/SUPG_News_2008_8_7_General_Releases.pdf
https://www.ncbi.nlm.nih.gov/pubmed/19432987
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21903282
Curator's Comment: description was created based on several sources, including
http://www.astx.com/content/resources/SUPG_News_2008_8_7_General_Releases.pdf
https://www.ncbi.nlm.nih.gov/pubmed/19432987
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=20563581
Curator's Comment: Known to be CNS penetrant in a non-human primate. Human data not available.
The plasma and cerebrospinal fluid (CSF) pharmacokinetics were studied in a non-human primate model that is highly predictive of CSF penetration in humans. CSF penetration is minimal
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL3717 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24326130 |
|||
Target ID: CHEMBL2007 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21903282 |
|||
Target ID: CHEMBL1936 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21903282 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
644 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22349808 |
360 mg 3 times / day multiple, oral dose: 360 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
29.5 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23178951 |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
81.7 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23178951 |
500 mg 3 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
174 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22349808 |
700 mg single, oral dose: 700 mg route of administration: Oral experiment type: SINGLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
|
61.5 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22349808 |
700 mg single, oral dose: 700 mg route of administration: Oral experiment type: SINGLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2321 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22349808 |
360 mg 3 times / day multiple, oral dose: 360 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
129 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23178951 |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
534 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23178951 |
500 mg 3 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
1472 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22349808 |
700 mg single, oral dose: 700 mg route of administration: Oral experiment type: SINGLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
|
674 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22349808 |
700 mg single, oral dose: 700 mg route of administration: Oral experiment type: SINGLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
11.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22349808 |
360 mg 3 times / day multiple, oral dose: 360 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
8.31 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22349808 |
700 mg single, oral dose: 700 mg route of administration: Oral experiment type: SINGLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
|
11.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22349808 |
700 mg single, oral dose: 700 mg route of administration: Oral experiment type: SINGLE co-administered: |
AMONAFIDE plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
5% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24326130 |
unknown, unknown |
AMUVATINIB serum | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
500 mg 2 times / day multiple, oral Highest studied dose Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Sources: Page: p.466 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.466 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
inconclusive [IC50 0.3034 uM] | ||||
weak [Inhibition 10 uM] | ||||
yes [IC50 2.1317 uM] | ||||
yes [IC50 4.7724 uM] | ||||
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
yes | ||||
yes | yes (co-administration study) Comment: Grapefruit juice increased Cmax and AUCtau by 52% and 55%. Sources: https://pubmed.ncbi.nlm.nih.gov/22349808/ |
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT01357395
Amuvatinib 300 mg three times a day + standard-of-care platinum-etoposide
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19432987
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.
Name | Type | Language | ||
---|---|---|---|---|
|
Official Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Code | English | ||
|
Systematic Name | English | ||
|
Systematic Name | English | ||
|
Code | English | ||
|
Code | English | ||
|
Code | English |
Classification Tree | Code System | Code | ||
---|---|---|---|---|
|
FDA ORPHAN DRUG |
262608
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
||
|
NCI_THESAURUS |
C1967
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
||
|
NCI_THESAURUS |
C129825
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
C71750
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
300000034057
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
WW-71
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
CHEMBL2103851
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
11282283
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
DB12742
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
9278
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
SO9S6QZB4R
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
850879-09-3
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
DTXSID50234176
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY | |||
|
C521047
Created by
admin on Fri Dec 15 15:59:53 GMT 2023 , Edited by admin on Fri Dec 15 15:59:53 GMT 2023
|
PRIMARY |
ACTIVE MOIETY
SALT/SOLVATE (PARENT)