Consider The Following Sar Data Acquired During The Optimisation Of A Kinase Inhibitor For The Target Tbk1 The Compound 1 (84.33 KiB) Viewed 13 times
Consider The Following Sar Data Acquired During The Optimisation Of A Kinase Inhibitor For The Target Tbk1 The Compound 2 (56.76 KiB) Viewed 13 times
Consider the following SAR data acquired during the optimisation of a kinase inhibitor for the target TBK1. The compounds are analogues of 5 where the substituents R1, R2, R3 are introduced using the substrates in the dashed box. R3 5 R2 mening R H R3 R2 R1 ОН CI CI H2N R1 R2 R3 Ph a d h Bno b Br e w OBn i MeOCH2CH20 j Ph f | с MeOCH2CH20 g -N k Analogue of 5 eg compound adk is: adk bdk cdk cek cfk TBK1 Binding Potency (K) 20 μM 2 μM 1 nM 6 nm 40 UM 12 uM 10 nM 4 nM 4 nM Ph cgk cdh cdi cdj
Discuss how you would develop this series into a PROTAC for the degradation of the target TBK1. You should explain, based on the SAR above, where on the TBK1 inhibitor you would include the linker to the E3 ligase binding ligand and how you would go about undertaking the optimisation of the PROTACs degradation potency.
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