Stress-free characterization
of a KRAS ternary complex
containing a covalent binder
KRAS — the protein mutated in colorectal and lung cancers — is not only
difficult to drug but its interactions with drug candidates are challenging
to study because KRAS isn't amenable to immobilization-dependent
measurements with SPR. And if the interaction involves a covalent binder,
your work got even more complicated and expensive because covalent
analytes are virtually impossible to remove from the sensor chip surface
during regeneration.
With measurements in solution, Dianthus removes the stress from studying
ternary complexes that involve a challenging target like KRAS and covalent
PROTAC LC-2. The formation of ternary a complex between KRAS
G12C
, PROTAC
LC-2, and VCB was successfully studied in solution by labeling ligase VCB,
which avoided disturbing finicky KRAS.
10
-5
10
-4
10
-3
10
-2
10
-1
10
0
10
1
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Ternary complex KRAS
G12C
+ LC-2 + VCB
Fraction
Bound
LC-2 (M)
K
d
= 4.4 nM S/N = 31.6
