Second-Generation JK-206 Targets the Oncogenic Signal Mediator RHOA in Gastric Cancer

Abstract

Ras homologous A (RHOA), a signal mediator and a GTPase, is known to be associated with the progression of gastric cancer (GC), which is the fourth most common cause of death in the world. Previously, we designed pharmacologically optimized inhibitors against RHOA, including JK-136 and JK-139. Based on this previous work, we performed lead optimization and designed novel RHOA inhibitors for greater anti-GC potency. Two of these compounds, JK-206 and JK-312, could successfully inhibit the viability and migration of GC cell lines. Furthermore, using transcriptomic analysis of GC cells treated with JK-206, we revealed that the inhibition of RHOA might be associated with the inhibition of the mitogenic pathway. Therefore, JK-206 treatment for RHOA inhibition may be a new therapeutic strategy for regulating GC proliferation and migration.

Molecular Landscape and Association With Crohn Disease of Poorly Cohesive Carcinomas of the Nonampullary Small Bowel

“…RHOA is a gene encoding for a member of the Rho family, a group of small GTPases with structural and signaling similarity to Ras proteins involved in the regulation of cytoskeletal dynamics, cell migration, and cell cycle, which has recently been identified as a promising therapeutic target in gastric cancer. 30 , 31 RHOA mutations have been described in gastric cancers, where they have been shown to be almost exclusively present in diffuse-type gastric carcinomas (14%-25%) 13 , 32 , 33 with the exception of a few intestinal-type/mixed-type gastric cancers (with anastomosing glands), 34 in appendiceal GCA, 35 and in some acute leukemias. 36 On the contrary, they seem to be extremely rare in colorectal adenocarcinoma (0.7%), as well as in other solid tumors.…”

Identification of immune‐related hub genes and construction of an immune‐related gene prognostic index for low‐grade glioma

“…The ras homologue family member A (RHOA) gene encodes a member of the Rho family of small GTPases 26 . When activated, it switches to an activated GTP‐bound form and promote actin cytoskeleton reorganization, which is associated with regulation of cell shape and multiple cellular functions 27,28 . RHOA has been demonstrated to be recurrently mutated in multiple types of cancer and played vital roles in the proliferation, migration and invasion of these tumour 29 .…”

“… 26 When activated, it switches to an activated GTP‐bound form and promote actin cytoskeleton reorganization, which is associated with regulation of cell shape and multiple cellular functions. 27 , 28 RHOA has been demonstrated to be recurrently mutated in multiple types of cancer and played vital roles in the proliferation, migration and invasion of these tumour. 29 RhoA has long been considered as an oncogene based on its mechanism of action by inducing RAS to transform into fibroblasts.…”

Identification of New L-Heptanoylphosphatidyl Inositol Pentakisphosphate Derivatives Targeting the Interaction with HIV-1 Gag by Molecular Modelling Studies

“…This outcome indicated that shorter H-bond and salt bridge formation distances between the phosphates of L-HIPPO with highly basic residues led to the participation of a molecule in a narrower space, thus the acyl chains were also embedded in a narrower hydrophobic region compared to BH-1 and BH-2. On the contrary, the settlement of BH-1 and BH-2 in MA with greater H-bond and salt bridge formation distances of the inositol ring and basic residues also led to the increase of occupation of acyl chains in a larger hydrophobic space in MA, enhancing the binding affinity of BH-1 and BH-2 in MA [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. These findings encouraged us to create a large library containing 213 new L-HIPPO derivatives containing distinct aromatic groups.…”