JNJ-3738

JNJ-3738 : Covalent Inhibitor of CDK7

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(2 ratings)

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Probe JNJ-3738 is in the process of SERP review.

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Information

CDK7

Covalent Inhibitor

up to 1 uM

Additional Data

SGC image SGC Chemical Probe Collection

In Vitro Validations

Uniprot ID: P50613

Target Class: Kinase

Target SubClass: CMGC

Potency Value: KIapp 31 nM

Potency Assay: Biochemical assay using CDK7/cyclinH/MAT1 complex (500 μM ATP; Kapp ~30 μM) (kinact = 0.0052/s; kinact/ KIapp 2603 M-1s-1)

PDB ID for probe-target interaction (3D structure): --

Target aliases:

Cyclin-dependent kinase 7, STK1, MO15, CDKN7, CAK1 ...

Other Reference: Peer reviewed at SGC

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): Selectivity within target family: Good CDK familiy selectivity: Closest family member is CDK9 (45 % inh.) vs CDK7 (95 % inh.) (activeXScreeen) > 100 times selectivity ActivX screen (combined output THP-1 & H1975 cell lysates (~280 kinases)): Closest off-targets at 1 µM [% inhibition]: CAMKK2 (70), STK16 (65). DiscoverX KinaseScreen at 1 µM: CDK7 (> 99 % inh., pIC50 = 8.42), CDK9 (36 % inh., pIC50 = 6.03). Selectivity outside target family: CEREP panel at 10 µM: Clean except for HRH1 (antagonist radioligand) 77% inh. Proteome-wide Selectivity-activity-based protein profiling (ABPP) (Jurkat): Closest off-target: PTGES2 (67 % inh.)

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 18 Dec 2024 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

JNJ-3738 is a potent, irreversible covalent inhibitor specifically targeting CDK7. It exhibits remarkable selectivity for CDK7 over other CDKs, due to its binding to the cysteine 312 residue unique to CDK7. This selectivity extends to both the kinome and the proteome, ensuring minimal off-target effects. In cell-based assays, at concentrations up to 1 µM, it is highly unlikely that any proteins/CDKs other than CDK7 will be targeted In all cell-based assays, it is essential to always include the negative control, JNJ-6240 (also recommended at 1 µM), to confirm on-target activity observed with JNJ-3738. To verify CDK7 modulation in cells, immunoblotting for phosphorylated CDK1 (T161), phosphorylated CDK2 (T160), and phosphorylated RNA polymerase II (Ser 5) should be conducted in disease-relevant cell lines. Based on available data, a reduction in the phosphorylation of these downstream targets of CDK7 can be observed after a 3-hour incubation with JNJ-3738. The probe is also suitable for in vivo studies, and when used at the recommended doses, off-target effects are unlikely. If feasible, using the negative control JNJ-6240 in vivo, in parallel with JNJ-3738, is recommended.

(last updated: 3 Feb 2025 )