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PROTAC THNAN69 degrades LIMK2, not LIMK1
A cereblon-recruiting degrader based on LIMKi3 and a phenyl dihydrouracil ligand wipes out LIMK2 at nanomolar DC50 while leaving LIMK1 and phospho-cofilin largely intact.
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What isoform-selective tool did the authors develop?
A LIMK2-specific PROTAC degrader (THNAN69).
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
What CRBN ligand replaced thalidomide, and why?
Phenyl dihydrouracil, to boost degradation potency and cut neo-substrate degradation.
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
What DC50s were measured in the EGFP–LIMK2 assay?
33 nM (21b), 13.7 nM (22c), 1 nM (THNAN69).
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
At what concentration is endogenous LIMK2 nearly gone with THNAN69 vs 21b?
10 nM versus 100 nM.
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
How selective was THNAN69 in a proteome-wide kinase sense?
LIMK2 was the only kinase selectively degraded (500 nM, 6 h, HuCCT1).
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
How did VHL PROTACs compare in cells?
Poor target engagement and poor cell penetrance versus CRBN analogues.
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
Does LIMK2 degradation collapse phospho-cofilin?
No—pCFL stays up, consistent with LIMK1 compensation.
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
What NanoBRET IC50 did THNAN69 show on LIMK2 vs LIMK1?
80 nM, five-fold stronger than LIMK1.
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
What control showed CRBN/CRL dependence?
No degradation with neddylation inhibitor or N-methyl inactive THNAN69-NC.
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
When is Dmax reached?
About 60 h after PROTAC treatment, with complete EGFP–LIMK2 loss.
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified
What structural idea explains isoform specificity?
More stable ternary complex and lysine accessibility on LIMK2 versus LIMK1.
Source: Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader · DOI · quote verified