BH-30236
A Multi-Targeted CLK Inhibitor
Our orally available, multi-targeted CLK inhibitor BH-30236 is designed to selectively modulate aberrant alternative splicing in cancerous tissue and shut down cancer’s ability to use off-target resistance mechanisms. We aim for BH-30236 to be applied to hematologic cancers and solid tumors. The first indications for its use are in treating adult AML and higher-risk myelodysplastic syndrome (HR-MDS).
The Need for a CLK Inhibitor
Alternative RNA splicing plays a crucial role in regulating various cellular processes, including development, differentiation, cell cycles, and cell death. When alternative splicing becomes dysregulated, it can significantly impact fundamental cellular functions, leading to the transformation of normal tissue into cancerous tissue, cancer progression, and even therapeutic resistance. In cancer cells, alternative splicing provides a mechanism for the development of treatment tolerance. Despite the potency or effectiveness of a cancer drug against a specific cancer-causing biological target, cancer can still adapt and resist treatment. This phenomenon is sometimes referred to as off-target resistance. Although the cellular machinery responsible for regulating alternative splicing is complex, research has consistently shown that aberrant alternative splicing is common in cancer. It occurs across various types of cancers. One notable player in this process is CDC-like kinases (CLK), a protein involved in modulating specific components of the cell’s splicing machinery that are involved in cancer tolerance and resistance.
RNA Splicing: A Mechanism of Off-Target Cancer Resistance
RNA splicing is an enzymatic process that occurs in the cell nucleus. During this process, a precursor mRNA (pre-mRNA) transcribed from a gene’s DNA sequence undergoes transformation into mature mRNA. This transformation involves excluding specific parts of the sequence (called introns) and joining together other parts (called exons). The mature mRNA is subsequently translated into a functional protein structure within the body.
The increase in diversity between the total number of known protein-coding genes and the total number of protein-coding mature mRNA transcripts can be partially attributed to RNA splicing. In certain cases, the stress induced by cancer therapy can upregulate signaling proteins, including anti-apoptosis proteins, which promote cancer cell survival. Notably, proteins like CDC-like kinases (CLK) play a role in regulating the cell’s splicing machinery, particularly concerning exon selection during pre-mRNA splicing. The regulation of these proteins involved in exon selection may counteract the changes that stressed cancer cells undergo to enhance their survival.
Addressing Relapsed or Refractory Adult Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndrome (HR-MDS)
Acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (HR-MDS) are hematologic cancers affecting approximately 30,000 new patients annually. While certain available treatments, such as those involving venetoclax, can effectively target AML and HR-MDS, a subset of patients develops resistance to standard-of-care treatments, leaving them with limited further options.
Research has revealed that proteins like CDC-like kinases (CLK) play a crucial role in regulating the cell’s splicing machinery, particularly concerning exon selection during pre-mRNA splicing. By modulating these proteins involved in exon selection, we may counteract the changes that stressed cancer cells undergo to promote their survival. At BlossomHill Therapeutics, we are actively developing an orally available, multi-targeted CLK inhibitor (BH-30236) designed to induce splicing alterations in cancerous tissue, promoting the expression of splicing isoforms that favor apoptosis, anti-proliferation, and anti-survival pathways, thereby disrupting the cancer’s ability to proliferate and exploit off-target resistance mechanisms.
More information about our clinical trial (NCT06501196) can be found on our Clinical Trials page.
