RAS mutants are involved in approximately 30% of all human
cancers and have been regarded as undruggable targets owing to relatively smooth
protein surface and obscure binding pockets. In our previous study, we have demonstrated that
GNF-7, a multi-targeted
kinase inhibitor, possesses potent anti-proliferative activity against Ba/F3 cells transformed with NRAS-G12D. Based on our further analysis using Ba/F3 cells transformed with mtRAS, we discovered a series of pyrimido[4,5-d]pyrimidin-2-one analogues as mtRAS-signaling pathway blockers. In addition, our efforts expanded the assessment to
cancer cells with mtRAS, which revealed that these substances are also capable of strongly suppressing the proliferation of various
cancer cells harboring KRAS-G12D (AsPC-1), KRAS-G12V (SW480, DU-145), KRAS-G12C (H358), KRAS-G13D (MDA-MB-231), KRAS-Q61L (HT-29), and NRAS-Q61L (OCI-AML3). We herein report novel and potent mtRAS-signaling pathway blockers, SIJ1795 and SIJ1772, possessing 2 to 10-fold increased anti-proliferative activities compared to those of
GNF-7 on
cancer cells harboring mtRAS as well as on Ba/F3 cells transformed with mtRAS. Both SIJ1795 and SIJ1772 attenuate phosphorylation of RAS downstream molecules (AKT and
MEK) and induce apoptosis and G0/G1 cell cycle arrest on
cancer cells with mtRAS. Moreover, both substances substantially suppress the migration, invasion, and colony formation of
cancer cells harboring mtRAS. Taken together, this study led us to identification of SIJ1795 and SIJ1772 capable of strongly inhibiting mtRAS-signaling pathway on
cancer cells harboring mtRAS.