Cdc42 is a protein involved in cell cycle regulation. Specifically, human Cdc42 is a small GTPase of the Rho family, which regulates the signaling pathways controlling various cell functions. Rho GTPases are the key to the assembly and rearrangement of the dynamic actin cytoskeleton, which is the basis of cell adhesion and migration. Besides, Cdc42 was overexpressed in NSCLC, colorectal adenocarcinoma, melanoma, breast cancer, and testicular cancer. Moreover, Cdc42 is essential for G1-S progression and mitosis, and it also regulates transcription factors SRF, STAT3, and NFkB.

Furthermore, the Overexpression of Cdc42 significantly enhanced the migration of cervical cancer cells. Meanwhile, Cdc42 promotes the expression of β1 integrin by activating a transcription factor called SRF. Persistent active forms of transcription factors can also insert endothelium into cancer cells lacking Cdc42. Nonetheless, the therapy targeting Rho GTPase Cdc42 signaling pathway in combination with chemotherapy may be an effective strategy for cancer treatment. Today, we will introduce a selective GTPase Cdc42 inhibitor, MLS-573151.

MLS-573151 is a Selective GTPase Cdc42 Inhibitor.

First of all, MLS-573151 is a selective GTPase Cdc42 inhibitor with an EC₅₀ of 2 μM. Obviously, MLS-573151 is inactive against other GTPases family members, such as Rab2, Rab7, H-Ras, Rac1, Rac 2, and RhoA wild-type. Particularly, MLS-573151 acts by blocking the binding of GTP to Cdc42.

In the second place, MLS-573151 (50 μM; for 15 min) reduced the fluorescence intensities of phagocytosed beads or bacteria in hemocytes. Importantly, MLS-573151 could effectively inhibit the phagocytic ability of granulocytes. MLS-573151 did not show any effect on ACEA-induced migration.

Last but not the least, for internalized FITC labeled beads or FITC labeled bacteria, the phagocytosis index of the MLS-573151 treated group was 3.0 times lower than that of the control group. In the case of casein, the inhibition of phagocytosis index decreased from 62% of FITC labeled inner beads to 35%. Interestingly, the phagocytic index of FITC labeled intrinsic bacteria decreased from 69% to 35%. However, the Cdc42 inhibitor had little effect on the phagocytic index of clear cells.

All in all, MLS-573151 is a selective GTPase Cdc42 inhibitor.

References:

Fan Mao, et al. Front Immunol. 2020 May 27;11:911.