Exploring the Therapeutic Potential of CTX-712 in Myeloid Neoplasms with Splicing Factor Mutations

Splicing factors are frequently mutated in myeloid cancers, particularly MDS and a subset of AML. Key mutations include SF3B1, SRSF2, U2AF1, and ZRSR2. These mutations are usually heterozygous and may have neomorphic effects, suggesting a potential for synthetic lethality. The serine/arginine-rich domains found in many splicing factors are phosphorylated by CLK family kinases, which are essential for mRNA splicing. Inhibition of these kinases can lead to reduced phosphorylation of SR proteins, altered splicing, and depletion of proteins involved in growth and survival pathways.

A recent study has shown that CLK inhibition can induce cell death and growth suppression, which is dependent on CLK2 expression levels. This has led to the development of CTX-712, a potent CLK inhibitor, which has been evaluated for its anti-leukemic activity in vitro and in vivo. CTX-712 has shown to inhibit the phosphorylation of multiple SR proteins in human myeloid cell lines.

In vivo studies using AML-derived xenograft models have demonstrated the efficacy of CTX-712. One model with an SRSF2 mutation responded significantly to the treatment, with complete remission achieved in 4 out of 5 mice treated with a high dose. Tumor volumes and survival rates were significantly improved in this model. Another model without SRSF2 mutations but carrying KRAS, NF1, and TP53 mutations also showed a significant reduction in leukemic burden after treatment.

CTX-712 has been shown to reduce AML tumors in a dose-dependent manner and improve survival in several PDX models. However, one model with multiple mutations, including U2AF1, was refractory to the treatment. Overall, CTX-712 has demonstrated anti-tumor effects in 4 out of 5 PDX AML models, with complete tumor disappearance in two cases.

These findings provide a rationale for further investigation of CLK inhibitors in MDS/AML and highlight the potential therapeutic target of CLK family kinases. CTX-712 is currently undergoing clinical trials for relapsed and refractory malignancies.