KRASG12D-HSP90 dual inhibitor

KRASG12D-HSP90 dual inhibitors are a class of heterobifunctional small molecules designed to simultaneously target the oncogenic KRAS G12D mutant and the molecular chaperone HSP90. Developed by Ranok Therapeutics, these compounds (such as RNK08179 and RNK08294) utilize a dual-targeting approach to overcome resistance to conventional KRASG12D inhibitors like MRTX1133. By inhibiting HSP90, which is preferentially activated in cancer cells, these agents promote the destabilization of substrate client proteins essential for tumor survival and bypass signaling. Preclinical studies in KRASG12D-mutated non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic cancer models have demonstrated that these dual inhibitors can induce apoptosis and suppress key downstream signaling pathways, including AKT and ERK1/2, even in models resistant to clinical-stage KRAS inhibitors. Notably, the HSP90 inhibitor moiety in the compound DI-2 is identical to onalespib.

Other names

KRASG12D-HSP90 heterobifunctional dual inhibitorKRASG-12D-HSP90 heterobifunctional dual inhibitorKRASG 12D-HSP90 heterobifunctional dual inhibitor