# Targeting KRAS in PDAC: A New Way to Cure It?
## 4 KRAS Inhibitors for PDAC
### Pan-RAS Inhibitors  
Compared to specific inhibitors, pan-RAS inhibitors have broader applicability and can provide treatment for patients with different types of KRAS mutations. Additionally, pan-RAS inhibitors can avoid drug resistance caused by the compensatory activation of wild-type KRAS. Although this class of inhibitors suffers from high toxicity and off-target inhibition, it still has great research potential [83]. Several pan-RAS inhibitors have been shown to have good specificity for RAS mutations, and animal models have tolerated these inhibitors to an appreciable degree [84; 85].  
[PERSON] et al. revealed that there are three distinct but equally populated conformations in the process of HRAS-GTP hydrolysis and nucleotide exchange, one of which is the \"non-signaling open conformation\" state [86]. Due to the same hydrolysis process and the structural homology, the state also appears in KRAS [87]. Using nuclear magnetic resonance (NMR) analysis, the researchers uncovered that the HRAS\({}^{\text{G60A}}\)-GppNp complex adopts an \"open conformation\" at the switch 1 region and abolishes the biological activity of HRAS [86; 88]. Recent studies have indicated extremely open switch 1 conformations of KRAS [89]. This implies that the \"open conformation\" may be a convergent point for survival signaling in KRAS-driven cancer, and agents locking this \"open conformation\" may theoretically block KRAS-dependent signaling. Most recently, [PERSON]'s group used a Specificity Affinity (SPA)-based virtual screening strategy to develop small-moleculeinhibitors that stabilize the \"open conformation\". This process led to the selection of three hits (NSC290956, NSC48693, and NSC48160) from 2000 compounds by individually docking compounds in the National Cancer Institute diversity compound sets to the \"open non-signaling intermediate conformation\" of RAS [89]. Of these, NSC290956 (also termed Spicolmazine or APY606) manifested potent efficacy against the proliferation of KRAS-driven pancreatic cancer cell lines CFPAC-1 (KRAS\({}^{\rm G12V}\)), MIA PaCa-2 (KRAS\({}^{\rm G12C}\)), Capan-1 (KRAS\({}^{\rm G12V}\)), SW1990 (KRAS\({}^{\rm G12T}\)) and BxPC-3 (wild-type KRAS) and pancreatic cancer cells but showed much less toxicity towards human normal cells [15; 90; 91]. NSC48160 inhibited the survival and growth of KRAS-driven pancreatic cancer cells CPFAC-1 (KRAS\({}^{\rm G12V}\)) and BxPC-3 (wild-type KRAS) by using MTT and colony-forming assays [16]. [PERSON] et al. found that NSC48160 selectively induced apoptosis in pancreatic cancer MIA PaCa-2 (KRAS\({}^{\rm G12C}\)) cells as compared to human normal HEK-293 and HL-7702 cells [92]. [PERSON] et al. further found that the inhibitory effects of small-molecule NSC48693 on KRAS-driven cancer cells were greater than NSC48160 for CFPAC-1(KRAS\({}^{\rm G12V}\)), MIA PaCa-2 (KRAS\({}^{\rm G12C}\)) and BxPC-3 (wild-type KRAS) cells [93]. Interestingly, the cytotoxic effect of NSC48693 on the human normal cell line (HL-7702) was lower than that on cancer cell lines (CFPAC-1, MIA PaCa-2 and BxPC-3). Together, this research provides functional insights into the \"open conformation\" and validates three hits acting as pan-KRAS inhibitors to induce the apoptosis of pancreatic cancer cells.