design of a lipid-like compound targeting KRAS4B-G12D through non-covalent bonds.

One of the most common drivers in human cancer is the peripheral membrane protein KRAS4B, able to promote oncogenic signalling. To signal, oncogenic KRAS4B not only requires a sufficient nucleotide exchange, but also needs to recruit effectors by exposing its effector-binding sites while anchoring to the phospholipid bilayer where KRAS4B-mediated signalling events occur. The enzyme phosphodiesterase-δ plays an important role in sequestering KRAS4B from the cytoplasm and targeting it to cellular membranes of different cell species. In this work, we present an design of a lipid-like compound that has the remarkable feature of being able to target both an oncogenic KRAS4B-G12D mutant and the phosphodiesterase-δ enzyme. This double action is accomplished by adding a lipid tail (analogous to the farnesyl group of the KRAS4B protein) to an previously known active compound (2-1,2,4-benzothiadiazine, 3,4-dihydro-,1,1-dioxide). The proposed lipid-like molecule was found to lock KRAS4B-G12D in its GDP-bound state by adjusting the effector-binding domain to be blocked by the interface of the lipid bilayer. Meanwhile, it can tune GTP-bound KRAS4B-G12D to shift from the active orientation state to the inactive state. The proposed compound is also observed to stably accommodate itself in the prenyl-binding pocket of phosphodiesterase-δ, which impairs KRAS4B enrichment at the lipid bilayer, potentially reducing the proliferation of KRAS4B inside the cytoplasm and its anchoring at the bilayer. In conclusion, we report a potential inhibitor of KRAS4B-G12D with a lipid tail attached to a specific warhead, a compound which has not yet been considered for drugs targeting RAS mutants. Our work provides new ways to target KRAS4B-G12D and can also foster drug discovery efforts for the targeting of oncogenes of the RAS family and beyond.