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. 2019 Jan 25;17:160–176. doi: 10.1016/j.csbj.2019.01.006

Table 2.

E3 protein ligand, structure of the linker and POI ligand with a description of the properties for kinases.

Table entry E3 protein (ligand) Linker POI ligand POI Potency/efficacy Reference
1. VHL (9) Image 28 Image 29 RIPK2 50% RIPK2 degradation at 1.4 nM after 1 hour. Dmax of >95% at 10 nM Bondeson [7]
2. VHL and CRBN (9 and pomalidomide) Image 30 imatinib, bosutinib, and dasatinib Tyrosine kinase: BCR-ABL >60% degradation at 1 μM for the dasatinib-CRBN PROTAC. No degradation for the VHL-based PROTACs. Lai [48]
3. CRBN (thalidomide) Image 31 Image 32 ERK1 and ERK2 In-cell click reaction where ERK1/2 degradation is observed partially after 4 h and is complete after 16 h at 10 μM Lebraud [84]
4. CRBN (thalidomide) n-pentyl Image 33 CDK9 Selective for CDK9. 56% degradation of CDK9 at 10 μM. Robb [95]
5. VHL (9) Diethylene glycol Lapatinib, gefitinib, afatinib RTKs: EGFR, HER2 and c-MET Efficient degradation of transmembrane RTKs with superior outcome over RTK inhibitors. Burslem [98]
6. CRBN (pomalidomide) Image 34 Image 35 Multi- kinase degrader Quantitative proteomics showed degradation of 28 kinases including BTK, FLT3 and nine members of the CDK family Huang [91]
7. CRBN (pomalidomide) Image 36 Image 37 BTK Most efficient degradation at 100 nM concentration. In addition, a bosutinib-based degrader was reported Huang [91]
8. CRBN (pomalidomide) Image 38 Image 39 FLT3 Concentrations between 10 and 100 nM resulted in the most efficient degradation of FLT3. Huang [91]
9. VHL (9) Image 40 Image 41 TBK1 Extensive linker optimization. DC50: 12 nM with Dmax: 96%. Crew [99]
10. CRBN (pomalidomide) Image 42 Image 43 CDK9 The multi target inhibitor SNS-032 became selective for CDK9 as PROTAC with near complete degradation at <250 nM concentration Olson [96]
11. CRBN (pomalidomide) Six different linkers were used. The best results were obtained with: Image 44 Image 45 PI3K IC50 for PI3K: 24 nM. time-/concentration-dependent degradation PI3K protein observed. Inhibition of HepG2 cell growth via autophagy Li [100]
12. CRBN (pomalidomide) Image 46 Image 47 ALK DC50: 3 and 11 nM respectively after 16 h in SU-DHL-1 cells. Potent inhibition of proliferation of SU-DHL-1 cells. Both linkers effective Zhang [101]
13. CRBN (pomalidomide) Image 48 Ceritinib and TAE684[108] ALK DC50 of 10 nM for both PROTACs in H3122 cells. ABCB1 was responsible for efflux. Powel [102]
14. CRBN (pomalidomide) Image 49 Image 50 CDK8 CDK8 IC50: 159 nM. Significant degradation of CDK8 in Jurkat cells after treatment for 24 hr at 1 μM concentration Hatcher [103]
15. CRBN (pomalidomide) Image 51 Image 52 BTK Efficiently degradation of BTK-WT. Induced degradation of ibrutinib-resistant BTK-C481S (50% degradation efficiency at 30 nM) Sun [104]
16. CRBN (5) Image 53 Image 54 BTK >99% degradation of mutated C481S and wildtype BTK at nM concentrations. Enhanced selectivity over ibrutinib Buhimschi [37]
17. CRBN (pomalidomide) Image 55 Image 56 BTK For n = 4 – 6 DC50’s between 1 and 40 nM. n = 1 – 3 are ineffective in degradation of BTK. Zorba [41]
18. CRBN (pomalidomide) Image 57 Image 58 CDK9 Serie 2 (n = 5) showed the most efficient CDK9 degradation in the concentration range of 1 to 30 μM. Inhibition of MCF cell proliferation with an IC50 of 17 μM Bian [97]
19. CRBN (pomalidomide) Image 59 Image 60 CK2 Most promising results for n = 2. Degradation of CK2 in a dose and time-dependent manner resulting in downstream reduced phosphorylation of Akt Chen [107]
20. VHL (9) Image 61 Image 62 ALK n = 1 displayed the best properties. 90% ALK degradation at 1 μM after 16 h. in SU-DHL-1 cells. Excellent efficacy in tumor xenograft mice. Kang [100]

The structure of the CRBN ligands and the VHL ligand (9) are shown in Fig. 2.