The Novel Small-Molecule SR18662 Efficiently Inhibits the Growth of Colorectal Cancer In Vitro and In Vivo

Krüppel-like factor 5 (KLF5), a member of the SP/KLF family of zinc finger transcription factors, is overexpressed in human colorectal cancer specimens, and this overabundance is associated with aggressive cancer development and progression. We demonstrated that mice haploinsufficient for Klf5 had reduced intestinal tumor burden in the background of germline mutation in Apc, a gatekeeper of intestinal tumorigenesis. Based on a high-throughput screening strategy, we developed ML264, a small-molecule compound that inhibits KLF5, and showed that it inhibits growth of colorectal cancer in vitro and in vivo Through optimization efforts based on the structure of ML264, we have now identified a new lead compound, SR18662. We find that treatment with SR18662 significantly reduces growth and proliferation of colorectal cancer cells as compared with treatment with vehicle control, ML264, or SR15006 (a less optimized analogue from SAR efforts leading to SR18662). SR18662 showed improved efficacy in reducing the viability of multiple colorectal cancer cell lines. Flow cytometry analysis following SR18662 treatment showed an increase in cells captured in either S or G2-M phases of the cell cycle and a significant increase in the number of apoptotic cells, the latter a unique property compared with ML264 or SR15006. SR18662 treatment also reduces the expression of cyclins and components of the MAPK and WNT signaling pathways. Importantly, we observed a significant dose-dependent inhibition of xenograft growth in mice following SR18662 treatment that exceeded the effect of ML264 at equivalent doses. These findings support further development of SR18662 and its analogues for colorectal cancer therapy.

 

Comments:

The information you provided describes a study on Krüppel-like factor 5 (KLF5) and its role in colorectal cancer. Here's a summary of the key findings:

1. Overexpression of KLF5: KLF5 is found to be overexpressed in human colorectal cancer specimens, and this overabundance is associated with aggressive cancer development and progression.

2. Reduced tumor burden in Klf5 haploinsufficient mice: Mice with reduced levels of Klf5 showed a decreased intestinal tumor burden when combined with a germline mutation in Apc, a gene known to be involved in intestinal tumorigenesis.

3. Development of ML264: A small-molecule compound called ML264 was developed as an inhibitor of KLF5 using a high-throughput screening strategy. ML264 was shown to inhibit the growth of colorectal cancer cells both in vitro (in cell cultures) and in vivo (in living organisms).

4. Identification of SR18662: Through optimization efforts based on the structure of ML264, a new lead compound called SR18662 was identified. SR18662 demonstrated improved efficacy compared to ML264 and SR15006 (an analogue of ML264).

5. Effects of SR18662 on colorectal cancer cells: Treatment with SR18662 significantly reduced the growth and proliferation of colorectal cancer cells compared to vehicle control, ML264, or SR15006. Flow cytometry analysis revealed an increase in cells captured in the S or G2-M phases of the cell cycle and a significant increase in apoptotic cells, which was unique to SR18662.

6. Pathway modulation: SR18662 treatment reduced the expression of cyclins (proteins involved in cell cycle regulation) and components of the MAPK and WNT signaling pathways, which are known to be dysregulated in colorectal cancer.

7. Inhibition of xenograft growth: In a mouse model of colorectal cancer, SR18662 demonstrated a significant dose-dependent inhibition of xenograft growth that exceeded the effect of ML264 at equivalent doses. This suggests that SR18662 may have stronger anti-tumor effects in vivo.

Based on these findings, the authors suggest that SR18662 and its analogues hold promise for further development as potential therapies for colorectal cancer.

Related Products

Cat.No.	Product Name	Information
S8900	SR18662	SR18662 is an optimized compund based on ML264 that inhibits Krüppel-like factor 5 (KLF5) with IC50 of 4.4 nM. SR18662 reduces the viability of multiple colorectal cancer cell lines. SR18662 induces apoptosis.

Related Targets

KLF