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Details

Stereochemistry ACHIRAL
Molecular Formula C29H28N4O2
Molecular Weight 464.5582
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of BI-847325

SMILES

CCNC(=O)C#CC1=CC2=C(C=C1)\C(C(=O)N2)=C(\NC3=CC=C(CN(C)C)C=C3)C4=CC=CC=C4

InChI

InChIKey=FLBNLJLONKAPLR-DQSJHHFOSA-N
InChI=1S/C29H28N4O2/c1-4-30-26(34)17-13-20-12-16-24-25(18-20)32-29(35)27(24)28(22-8-6-5-7-9-22)31-23-14-10-21(11-15-23)19-33(2)3/h5-12,14-16,18,31H,4,19H2,1-3H3,(H,30,34)(H,32,35)/b28-27-

HIDE SMILES / InChI
Molecular Formula C29H28N4O2
Molecular Weight 464.5582
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Description
Curator's Comment: Description was created based on several sources, including http://adisinsight.springer.com/drugs/800034007

BI-847325 is a novel, ATP-competitive, orally available inhibitor of Aurora kinases and MEK. In in vitro studies, BI-847325 inhibited the activity of Xenopus laevis Aurora Kinase B with an IC50 of 3 nM; with IC50 values for human Aurora kinase A and Aurora kinase C being 25 and 15 nM, respectively. BI-847325 also inhibited human MEK1 and MEK2 with respective IC50 values of 25 and 4 nM. BI-847325 had been in phase I clinical trials by Boehringer Ingelheim for the treatment of solid tumours. However, there is no development reported for this study.

Originator

Approval Year

Unknown
139594
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8297
 25.0 nM [IC50]
Inhibitor
8297
 15.0 nM [IC50]
Inhibitor
8297
 25.0 nM [IC50]
Inhibitor
8297
 4.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Approved
8429
Unknown

Approved Use

Unknown
PubMed

PubMed

TitleDatePubMed
The Novel ATP-Competitive MEK/Aurora Kinase Inhibitor BI-847325 Overcomes Acquired BRAF Inhibitor Resistance through Suppression of Mcl-1 and MEK Expression.
2015 Jun
Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases.
2016 Oct
Patents

Patents

20110263565
1

Sample Use Guides

In Vivo Use Guide
Mice: In mice bearing 1205Lu and 1205LuR xenografts, BI-847325 (75 mg/kg, p.o.) causes significant tumor suppression without significant alteration in the body weights.
Route of Administration: Oral
In Vitro Use Guide
BI-847325 inhibited BRAF-mutant and vemurafenib-resistant melanoma cells with IC50 ranging from 0.3 nM to 2 uM, and prevents colony formation in six BRAF-mutant melanoma cell lines. Treatment of the cell line panel with BI-847325 (30–300 nM, 28 days) prevented colony formation in 6 BRAF-mutant melanoma cell lines. The growth inhibitory effect of BI-847325 (48h, 1 uM) was also associated with apoptosis induction, with significant levels of cell death being seen at concentrations >100 nM
Substance Class Chemical
Created
by admin
on Sat Dec 16 18:27:02 GMT 2023
Edited
by admin
on Sat Dec 16 18:27:02 GMT 2023
Record UNII
QXD8ZW7UVZ
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
BI-847325
Code English
BI847325
Code English
3-(3-(((4-((DIMETHYLAMINO)METHYL)PHENYL)AMINO)PHENYLMETHYLENE)-2,3-DIHYDRO-2-OXO-1H-INDOL-6-YL)-N-ETHYL-2-PROPYNAMIDE
Systematic Name English
3-((3Z)-3-(((4-((DIMETHYLAMINO)METHYL)PHENYL)AMINO)(PHENYL)METHYLENE)-2-OXO-2,3-DIHYDRO-1H-INDOL-6-YL)-N-ETHYL-2-PROPYNAMIDE
Systematic Name English
2-PROPYNAMIDE, 3-(3-(((4-((DIMETHYLAMINO)METHYL)PHENYL)AMINO)PHENYLMETHYLENE)-2,3-DIHYDRO-2-OXO-1H-INDOL-6-YL)-N-ETHYL-
Systematic Name English
3-((3Z)-3-((4-(DIMETHYLAMINOMETHYL)ANILINO)-PHENYL-METHYLENE)-2-OXO-INDOLIN-6-YL)-N-ETHYL-PROP-2-YNAMIDE
Systematic Name English
2-PROPYNAMIDE, 3-((3Z)-3-(((4-((DIMETHYLAMINO)METHYL)PHENYL)AMINO)PHENYLMETHYLENE)-2,3-DIHYDRO-2-OXO-1H-INDOL-6-YL)-N-ETHYL-
Systematic Name English
Code System Code Type Description
MANUFACTURER PRODUCT INFORMATION
BI-847325
Created by admin on Sat Dec 16 18:27:02 GMT 2023 , Edited by admin on Sat Dec 16 18:27:02 GMT 2023
PRIMARY BI-847325: Item NO. 18301, CAS NO. 1207293-36-4BI-847325 is a selective dual MEK/Aurora kinase inhibitor with IC50 values of 3, 25, 15, 25, and 4 nM for X. laevis Aurora B, human Aurora A and Aurora C, and human MEK1 and MEK2, respectively. It can inhibit the growth and survival of both treatment-naive and drug-resistant melanoma cell lines, decreasing the expression of MEK and Mcl-1 while increasing the expression of pro-apoptotic protein Bim.1 At 70 mg/kg, BI-847325 induces apoptosis in treatment-naive and drug-resistant xenografted melanoma in vivo.
CAS
1207293-36-4
Created by admin on Sat Dec 16 18:27:02 GMT 2023 , Edited by admin on Sat Dec 16 18:27:02 GMT 2023
NON-SPECIFIC STEREOCHEMISTRY
PUBCHEM
54577344
Created by admin on Sat Dec 16 18:27:02 GMT 2023 , Edited by admin on Sat Dec 16 18:27:02 GMT 2023
PRIMARY
SMS_ID
100000178383
Created by admin on Sat Dec 16 18:27:02 GMT 2023 , Edited by admin on Sat Dec 16 18:27:02 GMT 2023
PRIMARY
CAS
2128698-24-6
Created by admin on Sat Dec 16 18:27:02 GMT 2023 , Edited by admin on Sat Dec 16 18:27:02 GMT 2023
PRIMARY
FDA UNII
QXD8ZW7UVZ
Created by admin on Sat Dec 16 18:27:02 GMT 2023 , Edited by admin on Sat Dec 16 18:27:02 GMT 2023
PRIMARY
Related Record Type Details
Structure of BI-847325
ACTIVE MOIETY
Originator: Boehringer Ingelheim; Class: Antineoplastic; Mechanism of Action: Aurora kinase A inhibitor, Aurora kinase B inhibitor, Aurora kinase C inhibitor, Mitogen-activated protein kinase inhibitor; Orphan Drug Status: No; On Fast track: No; New Molecular Entity: Yes; Highest Development Phase: No development reported for Solid tumours; Most Recent Events: 16 Jul 2016 No recent reports of development identified for phase-I development in Solid-tumours in Belgium (PO), 01 Oct 2013 Boehringer Ingelheim completes a phase I trial in Solid tumours in Belgium (NCT01324830), 31 Mar 2011 Phase-I clinical trials in Solid tumours in Belgium (PO)
Structure of BI-847325
ACTIVE MOIETY
Results: Sixty-nine patients (Schedule A, n = 47, Schedule B, n = 22) were treated. The MTD was 120 mg per day for Schedule A (cumulative dose of 1680 mg per 3-week cycle) and 150 mg per day for Schedule B (cumulative dose of 2250 mg per 3-week cycle). Reversible hematologic and gastrointestinal toxicities were the most common dose-limiting toxicities. One patient with esophageal cancer (receiving 160 mg BI 847325, Schedule A) experienced a partial response for 67 days, and 21 patients (n = 11 (23.4 %), Schedule A, n = 10 (45.5 %), Schedule B) had stable disease. Pharmacokinetic analyses showed at least bi-exponential disposition, with high inter-subject variability. There was no obvious relationship between markers of MEK or Aurora kinase inhibition and exposure to BI 847325 (exploratory analysis). Conclusions: This first-in-human trial suggests that BI 847325 has an acceptable safety profile. However, due to insufficient drug exposure at the MTD to achieve relevant MEK inhibition, a decision was taken to halt the development of BI 847325.
Structure of BI-847325
ACTIVE MOIETY
Official Title: An Open Label Phase Ia/Ib Study of Two Dosing Schedules of BI 847325, Orally Administered Once a Day in Patients With Advanced Solid Tumours, With Repeated Cyclic Administration in Patients With Clinical Benefit Purpose: The aim of the Phase Ia (dose escalation) part of this trial is to assess the MTD of BI 847325 administered at escalating doses in 2 treatment arms. In the Phase Ib expansion part of the trial, the aim is to further evaluate the safety profile of BI 847325 at the recommended dose and schedule and to assess target modulation and the potential antitumour efficacy in patients with selected tumour types.
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