The novel small molecule SR18662 efficiently inhibits the growth of colorectal cancer in vitro and in vivo.

Kruppel-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 gate keeper 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 (CRC) in vitro and in vivo. Through optimization efforts based on structure of ML264, we have now identified a new lead compound, SR18662. We find that treatment with SR18662 significantly reduces growth and proliferation of CRC cells as compared to treatment with vehicle control, ML264, or SR15006 (a less optimized analogue from SAR efforts leading to SR18662). SR18662 showed improved efficacy in reducing viability of multiple CRC 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 to ML264 or SR15006. SR18662 treatment also reduces the expression of cyclins and components of 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.