Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C15H18BrN7 |
| Molecular Weight | 376.254 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1C=C(C=N1)C2=C3N=C([C@H]4CCCNC4)C(Br)=C(N)N3N=C2
InChI
InChIKey=GMIZZEXBPRLVIV-VIFPVBQESA-N
InChI=1S/C15H18BrN7/c1-22-8-10(6-19-22)11-7-20-23-14(17)12(16)13(21-15(11)23)9-3-2-4-18-5-9/h6-9,18H,2-5,17H2,1H3/t9-/m0/s1
MK-8776 (SCH-900776) is a checkpoint kinase 1 inhibitor which was developed by Merck for the treatment of cancer. The drug was tested in phase II clinical trials on patients suffering from acute myeloid leukemia (in combination with cytarabine) and in phase I on patients suffering from solid tumors or lymphoma (as monotherapy and in combination with gemcitabine).
Originator
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL4630 |
3.0 nM [IC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
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| Primary | Unknown Approved UseUnknown |
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| Primary | Unknown Approved UseUnknown |
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| Primary | Unknown Approved UseUnknown |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1010 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
20 mg/m² single, intravenous dose: 20 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
6220 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
150 mg/m² single, intravenous dose: 150 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
1220 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
40 mg/m² single, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
4970 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
80 mg/m² single, intravenous dose: 80 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
4680 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
200 mg single, intravenous dose: 200 mg route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1420 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
20 mg/m² single, intravenous dose: 20 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
19000 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
150 mg/m² single, intravenous dose: 150 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
2250 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
40 mg/m² single, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
5060 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
80 mg/m² single, intravenous dose: 80 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
8410 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
200 mg single, intravenous dose: 200 mg route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
7.28 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
20 mg/m² single, intravenous dose: 20 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
9.18 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
150 mg/m² single, intravenous dose: 150 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
7.67 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
40 mg/m² single, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
7.38 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
80 mg/m² single, intravenous dose: 80 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
6.28 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
200 mg single, intravenous dose: 200 mg route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
51% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25605849/ |
40 mg/m² single, intravenous dose: 40 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MK-8776 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
112 mg/m2 single, intravenous (unknown) Highest studied dose Dose: 112 mg/m2 Route: intravenous Route: single Dose: 112 mg/m2 Sources: |
unhealthy n = 8 Health Status: unhealthy Condition: Advanced Solid Tumors Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: |
|
150 mg/m2 single, intravenous (unknown) Highest studied dose Dose: 150 mg/m2 Route: intravenous Route: single Dose: 150 mg/m2 Sources: |
unhealthy n = 3 Health Status: unhealthy Condition: Advanced Solid Tumors Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. | 2011 Apr |
|
| Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias. | 2012 Dec 15 |
|
| Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites. | 2012 Feb |
|
| Decreased translation of p21waf1 mRNA causes attenuated p53 signaling in some p53 wild-type tumors. | 2012 May 1 |
|
| Unique functions of CHK1 and WEE1 underlie synergistic anti-tumor activity upon pharmacologic inhibition. | 2012 Nov 13 |
|
| Effects of selective checkpoint kinase 1 inhibition on cytarabine cytotoxicity in acute myelogenous leukemia cells in vitro. | 2012 Oct 1 |
|
| Combination therapy targeting the Chk1 and Wee1 kinases shows therapeutic efficacy in neuroblastoma. | 2013 Jan 15 |
|
| The novel Chk1 inhibitor MK-8776 sensitizes human leukemia cells to HDAC inhibitors by targeting the intra-S checkpoint and DNA replication and repair. | 2013 Jun |
|
| MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. | 2016 Nov 1 |
Patents
Sample Use Guides
Patients receive cytarabine IV continuously over 72 hours on days 1-3 and 10-12 and Chk1 inhibitor MK-8776 IV over 30 minutes on days 2, 3, 11, and 12.
Route of Administration:
Intravenous
U937 cells were treated (a) for 4 h with combination of cytarabine (50 nM) and MK-8776 (100, 200, 300, 500 nM); (b) for 4 h with cytarabine (0, 5, 10 nM) in the absence or presence of 100; (c) for 24 h with diluent (0.2% DSMO), 50 nM cytarabine, 100 or 300 nM to test the effect of MK-8776 on cytarabine-induced replication checkpoint activation. HL-60 cells were treated (a) for 24 h with diluent (0.2% DMSO), 300 nM cytarabine, 300 nM MK-8776 or 300 nM cytarabine + 300 nM MK-8776; (b) for 24 h with cytarabine (0, 100, 300 nM) in the presence of MK-8776 at 100, 300 or 1000 nM to test how MK-8776 enhances cytarabine-induced apoptosis in human AML cell lines. In the same experiment, ML-1 cells were also treated for 24 h with cytarabine (50-250 nM) and MK-8776 (0, 25, 50, 100 nM).
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