CLK inhibitor BH-30236

An orally bioavailable macrocyclic ATP-competitive inhibitor of CDC2-like kinase (CLK) family kinases, including CLK1, CLK2 and CLK4, with potential antineoplastic activity. Upon oral administration, CLK inhibitor BH-30236 targets, binds to and inhibits the activity of CLK1/2/4, thereby inhibiting the phosphorylation of serine/arginine-rich (SR) domain-containing splicing factors (SFs). This modulates RNA splicing, prevents the expression of certain tumor-associated genes, and inhibits tumor cell proliferation. In many cancer cells, core spliceosome proteins, including SF3B1, U2 small nuclear ribonucleoprotein auxiliary factor 1 (U2AF1), serine/arginine-rich splicing factor 2 (SRSF2) and U2 small nuclear ribonucleoprotein auxiliary factor subunit-related protein 2 (ZRSR2), are mutated and aberrantly activated leading to a dysregulation of mRNA splicing. CLK family kinases, an evolutionarily conserved group of kinases, phosphorylates various SR proteins including SR domain-containing SFs.