CM11

Degrader (PROTAC) of VHL

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(0 ratings)

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Information

Degrader (PROTAC)

10-500 nM

DOI - 10.1038/s41467-017-00954-1

Probe Availability:

In Vitro Validations

Uniprot ID: P40337

Target Class: Other post-translational modification

Target SubClass: E3 ubiquitin ligase

Potency: Kd

Potency Value: 10 nM

Potency Assay: ITC

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

Target aliases:

von Hippel-Lindau disease tumor suppressor, VHL, V ...

DOI Reference: 10.1038/s41467-017-00954-1

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

Kinase off-target screening results. CM11 was screened at 1 μM concentration against a panel of 50 kinases (Dundee MRC-PPU Express Screen, http://www.kinase-screen.mrc.ac.uk/services/express- screen). The remaining kinase activity was recorded at the end of the assay. The data is reported as average % activity remaining of assay duplicates for each kinase tested (± standard deviation in brackets), ranked from highest to lowest. Plate Barcode CM11 D6769PM 1uM % activity (s.d.) RIPK2 130 (37) VEG-FR 126 (17) MKK1 126 (2) IGF-1R 118 (14) HER4 115 (11) CHK2 114 (3) MARK3 113 (3) SYK 113 (28) MLK3 112 (2) TAK1 112 (2) TBK1 112 (8) BTK 112 (5) MST2 111 (3) Lck 111 (2) HIPK2 111 (9) EF2K 110 (9) PDK1 109 (8) SmMLCK 109 (3) JAK3 108 (2) JNK1 108 (1) ROCK 2 108 (8) IRAK4 107 (5) CK1δ 107 (4) PIM1 107 (1) MSK1 106 (8) NEK6 106 (4) EPH-A2 105 (11) CAMK1 105 (5) PRK2 104 (7) LKB1 104 (5) PKD1 103 (10) p38a MAPK 102 (1) GSK3b 101 (2) DYRK1A 100 (4) AMPK (hum) 100 (11) CK2 100 (3) CAMKKb 99 (3) PKBa 97 (8) SRPK1 97 (12) PLK1 97 (4) S6K1 97 (7) RSK1 96 (6) Aurora B 96 (8) Src 95 (10) PKCa 95 (1) SGK1 95 (5) PKA 90 (5) PAK4 90 (10) TTK 89 (2) TrkA 89 (4)

Potency assay, off target (cells): To evaluate the specificity of homo-PROTAC-induced degradation, and identify potential off-targets, we performed isobaric tagging mass spectrometry proteomics to quantify degradation at the proteome level in an unbiased fashion. Amongst the 6,450 detected proteins that passed filtering criteria no proteins other than Cul2 was substantially depleted by homo-PROTACs CM09, CM10 or 6 compared to DMSO or VHL inhibitor treatment. Crucially, no effect on protein levels of other Cullins (Cul1, Cul3, Cul4A, Cul4B, Cul5 and Cul7) or CRL-associated subunits was observed. Together, the data demonstrate that CM11 mainly induce depletion of pVHL30 and Cul2 but not other proteins. The proteomics data further evidenced no increase in protein levels of HIF-1α with homo-PROTACs (but a small decrease with CM09) relative to DMSO (Supplementary Fig. 6). In contrast, treatment with 150 μM VH032 led to increased HIF-1α levels, as expected.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

A negative control known as CMP-98 is available and should be used when testing the activity of CM-11.

(last updated: 15 Apr 2020 )

SERP Ratings

In Cell Rating

(last updated: 15 Apr 2020 )

SERP Ratings

In Cell Rating

SERP Comments:

CM11 is a potent and selective degrader of VHL that will induce auto-degradation of VHL in compatible cell lines. To distinguish inhibition versus degradation effects complenetary use of a VHL inhibitor such as VH 298 is recommended.

(last updated: 1 May 2020 )