Table 1 Effect of linker on activity of p53-Y220C–PLK1 bifunctionals

From: Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs

Linker

Length (Å)

Linker type

Competition EC50 (µM)

NanoBiT EC50 (µM)

PEG2

10.96

PEG

2.13

2.45

PEG4

16.01

PEG

0.85

2.12

PEG6

22.22

PEG

0.90

3.68

C12

12.71

Alkyl

NA

NA

C6

8.08

Alkyl

0.12

0.48

C3

4.33

Alkyl

0.025

0.41

Nipecotic acid

5.96

Rigid

33.2

1.24

Phenylpiperidine

9.35

Rigid

NA

6.28

Azaspiroheptane

6.14

Rigid

0.101

0.44

  1. Summary of linkers tested. The linker length, EC50 from Halo–p53-Y220C ΔTAD–mCherry versus parental 293T growth competition and EC50 from NanoBiT experiment are listed (n = 3 replicates per condition for viability competition; n = 4 replicates per condition for NanoBiT). Growth competition assays were analyzed on day 10. NanoBiT experiments were set up in 293T cells cotransfected with NLS–LgBiT–p53-Y220C (DBD) and mEGFP–PLK1–SmBiT, treated with compound for 24 h. NA indicates that the EC50 could not be computed because of a lack of potency.
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