Figure 6. Ligand optimization for Rab and Rho GTPases.

(A and B) Representative binding poses from covalent MD simulations of divarasib, and selected ligands in Rac1(G12C) (A) and Rab5C(S30C) (B), respectively.

(C) Chemical structures of novel SII pocket inhibitors to improve targeting of Rab and Rho GTPases.

(D) Covalent modification of Rac1(G12C) with compounds 1–22 (50 μM, 1 h).

(E) Covalent modification of Rab1A(S20C) with compounds 1–22 (50 μM, 1 h).

(F) Covalent modification of Rab5C(S30C) with compounds 1–22 (50 μM, 12 h).

See also Figures S5 and S6.