Meeting a new mechanism

SAN DIEGO—In late 2019, Samumed, LLC noted the publication of data demonstrating a novel mechanism of action for SM08502 in preclinical gastrointestinal cancer models. The article, entitled “The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models,” was published in the journal Cancer Letters.

“SM08502 is a CDC-like kinase (CLK) inhibitor and … a potent inhibitor of CLK2 and CLK3. “This publication shows that both CLK2 and CLK3 are oncogenic kinases, meaning they help to drive the formation of cancer through the activation of key pathways, including, as Samumed discovered, the Wnt signaling pathway,” says Dr. Yusuf Yazici, chief medical officer of Samumed. “Through this CLK inhibition, SM08502 can reduce Wnt pathway activity, which is aberrantly activated in 90 percent of colorectal cancers. More specifically, these data show that SM08502’s Wnt pathway inhibition occurs via the disruption of alternate splicing of key Wnt-related genes, resulting in their reduced expression.”

“Due to its mechanism of action inhibiting CLK, SM08502 has the potential to treat many different types of solid tumors beyond gastrointestinal tumors, including pancreatic cancer (for which SM08502 received orphan drug designation from the FDA in January 2019), prostate cancer, breast cancer, gastric cancer and hepatocellular carcinoma,” he continues.

Regulation of CLK2 and CLK3 is a novel strategy that leads to modulation of Wnt pathway signaling in cancer. The paper focuses on SM08502, currently being evaluated in a Phase 1 study in the U.S. The study is designed to assess the safety and pharmacokinetics of SM08502 in patients with multiple types of advanced solid tumors.

According to Yazici, “It is well documented that aberrant Wnt pathway signaling occurs in many types of cancer, including around 90 percent of colorectal cancers, but the complexity of the Wnt signaling pathway has presented challenges for developing safe and efficacious Wnt signaling modulators for cancer treatment to date.”

“These published data identified a novel mechanism for impacting Wnt pathway signaling via potent inhibition of CLK2 and CLK3 and subsequent effects on alternative splicing. Our first-in-class CLK inhibitor, SM08502, had strong antitumor effects and diminished aberrant Wnt pathway activity in these mouse models and demonstrated its potential to treat gastrointestinal cancers,” he added. “We look forward to the availability of data from our ongoing Phase 1 safety and pharmacokinetics trial in subjects with advanced solid tumors.”

Data highlights of the study include the information that CLK3 is a potential oncogenic kinase, as has been reported for CLK2. SM08502 inhibited the Wnt signaling pathway, both in vitro and in vivo, in colorectal cancer models. Inhibition of CLK2 and CLK3 affected alternative splicing, which underlies inhibition of aberrant Wnt signaling. SM08502 also demonstrated significant anti-tumor effects in xenograft models of gastrointestinal cancer.

The article points out that “SM08502 inhibited serine and arginine rich splicing factor (SRSF) phosphorylation and disrupted spliceosome activity, which was associated with inhibition of Wnt pathway-related gene and protein expression. Additionally, SM08502 induced the generation of splicing variants of Wnt pathway genes, suggesting that its mechanism for inhibition of gene expression includes effects on alternative splicing. Orally administered SM08502 significantly inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation and Wnt pathway gene expression in xenograft mouse models.”

“When compared to selective targeting of CLK2 alone using CC-671, the addition of CLK3 inhibition with SM08502 induced stronger inhibition of both SRSF phosphorylation and Wnt pathway gene expression in vitro. This may explain why CLK2 and CLK3, individually, have not been previously identified in genome-wide screens as regulators of the Wnt/β-catenin pathway. Like CLK2, which has been identified as an oncogene in breast cancer, CLK3 is a potential oncogenic kinase, given the profound inhibition of tumor growth in CRISPR-generated CLK3 KO SW480 clones,” the authors write. “Knockdown of CLK3 in these clones demonstrated inhibition of SRSF6 phosphorylation despite the presence of CLK1 or CLK2, which further supports the importance of CLK3 inhibition for the overall anti-tumor mechanism of SM08502.”

“Not only did this study highlight the potential of SM08502 for the treatment of gastrointestinal tumors, but it also highlights the expertise of Samumed’s scientists in the study of Wnt signaling mechanisms,” Yazici notes. “As such, an important discovery from the development of SM08502 is the identification of a previously unknown method for reducing Wnt signaling in tumors, through CLK. If the preclinical results ... showing anti-tumor effects in mice translate into humans, SM08502 could represent an important breakthrough not only for the treatment of gastrointestinal tumors, but also for the broad development of Wnt-targeting drugs.”

“The Phase 1 study ... is currently ongoing. Top-line results are expected in 2020. After the Phase 1 dose escalation study, we plan to expand into multiple indications for SM08502, including but not limited to gastrointestinal malignancies, starting in 2020,” he concludes.