MK-2048

Catalog No.S2765 Batch:S276501

Technical Data

Formula	C₂₁H₂₁ClFN₅O₄
Molecular Weight	461.87	CAS No.	869901-69-9
Solubility (25°C)*	In vitro	DMSO	9 mg/mL (19.48 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

MK-2048 is a potent inhibitor of integrase (IN) and IN_R263K with IC50 of 2.6 nM and 1.5 nM, respectively.

Targets

Integrase (R263K) ^[1]	Integrase ^[1]
1.5 nM	2.6 nM

In vitro

MK-2048 inhibits subtype B and subtype C integrase activities with IC50 of 75 nM and 80 nM, respectively. Disintegration is prevented by high concentrations of MK-2048 to a comparable extent with both subtype B and C enzymes. Mutation at the site of R263K slightly increases integrase susceptibility to MK-2048. G118R translates into a decrease in integrase activity and confers resistance to MK-2048. ^[2] MK-2048 inhibits S217H intasome with an IC50 of 900 nM. By contrast, MK2048 remains fully active against the N224H intasome with an IC50 of 25 nM. MK2048 displays substantially lower dissociation rates compared with raltegravir, another integrase inhibitor. ^[3] The subsequent selection of E138K partially restores replication capacity to approximately 13% of wt levels and increased resistance to MK-2048 to approximately 8-fold. MK-2048 is active against viruses resistant to RAL and EVG. Exposure to MK-2048 leads to the selection of G118R as a possible novel resistance mutation after 19 weeks. Continued pressure with MK-2048 subsequently leads to an additional substitution after 29 weeks at position E138K, within the IN gene. Although the G118R mutation alone confers only slight resistance to MK-2048 but not to RAL or EVG, its presence arouses a dramatic reduction in viral replication capacity compared to wild-type NL4-3. E138K both partially restores viral replication capacity and also contributes to increased levels of resistance against MK-2048. ^[4]

Protocol (from reference)

Cell Assay:^{^[4]}	Cell lines PM1 cells Concentrations 0.0256 nM to 2 μM Incubation Time 72 hours Method A total of 7.5×10⁴ PM1 cells per well are infected with clonal NL4-3 virus containing the integrase mutations G118R, E138K, or G118R and E138K or with wild-type viruses (45 ng p24 virus per well) by spinoculation at 1,200 × g for 2 hours at 37 °C. Cells are washed twice to remove unbound virus and then resuspends in RPMI growth medium alone or containing various concentrations of MK-2048, ranging between 0.0256 nM and 2 μM. Experiments is performed, each in duplicate. Supernatant reverse transcriptase (RT) activity is measured at 72 hours postinfection as an indicator of virus replication. Data are normalized based on uninfected and no-drug controls included in each experiment. Viral replication capacity is determined in PM1 cells using the same methodology as that used to determine EC50s, by comparing levels of supernatant RT activity of each mutant virus to those of wild-type virus in the absence of MK-2048.

Cell Assay:^{^[4]}

Cell lines
PM1 cells
Concentrations
0.0256 nM to 2 μM
Incubation Time
72 hours
Method
A total of 7.5×10⁴ PM1 cells per well are infected with clonal NL4-3 virus containing the integrase mutations G118R, E138K, or G118R and E138K or with wild-type viruses (45 ng p24 virus per well) by spinoculation at 1,200 × g for 2 hours at 37 °C. Cells are washed twice to remove unbound virus and then resuspends in RPMI growth medium alone or containing various concentrations of MK-2048, ranging between 0.0256 nM and 2 μM. Experiments is performed, each in duplicate. Supernatant reverse transcriptase (RT) activity is measured at 72 hours postinfection as an indicator of virus replication. Data are normalized based on uninfected and no-drug controls included in each experiment. Viral replication capacity is determined in PM1 cells using the same methodology as that used to determine EC50s, by comparing levels of supernatant RT activity of each mutant virus to those of wild-type virus in the absence of MK-2048.

References

[4] Bar-Magen T, et al. J Virol. 2010, 84(18), 9210-9216.

+ Expand

Selleck's MK-2048 has been cited by 5 publications

Targeting the Integrated Stress Response Kinase GCN2 to Modulate Retroviral Integration [ Molecules, 2021, 26(17)5423]	PubMed: 34500856
Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that Can Be Exploited by Targeting DNA Polymerase ε [ Mol Cell, 2020, S1097-2765(20)30723-1]	PubMed: 33152268
Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1-infected cells. [ Blood Adv, 2020, 12;4(9):1845-1858]	PubMed: 32369565
Discovery of Novel Integrase Inhibitors Acting outside the Active Site Through High-Throughput Screening. [ Molecules, 2019, 24(20)]	PubMed: 31614773
Loss of ARID1A promotes proliferation, migration and invasion via the Akt signaling pathway in NPC [ Cancer Manag Res, 2019, 11:4931-4946]	PubMed: 31213911

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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