We are proceeding Research & Development to deliver the world’s first in class anti-cancer drug from Japan.
1. Our Research
At our core, we are a science-driven start-up developing next generation small-molecule inhibitor for cancer treatment. The Chordia pipeline is built on our expertise in RNA deregulation, a newly-proposed hallmark of cancer. Recent research highlights that RNA processing is systematically altered in cancer, demonstrating the pivotal influence of RNA deregulation on tumorigenesis, growth and progression. We aim to develop life-changing treatments for cancer by generating small-molecule medicines that prevent or modify RNA deregulation. We collaborate with academic researchers on cutting-edge next-generation sequencing and gene-editing systems to thoroughly understand neoplastic disease states involving RNA deregulation, drive the discovery of novel therapeutic targets, and define patient selection strategies. Combining these strategies increases the probability that our pipeline will successfully derive beneficial therapeutic effects for patients with cancer.
2. “RNA Deregulation” A Novel Hallmark of Cancer
Cancer’s remarkable diversity had beenunderstood through a logical framework of six key hallmarks. Additionally, several equally prevalent hallmarks have been identified in recent analyses of cellular phenotypes. Although these cancer phenotypes are not responsible for initiating tumorigenesis, they are common characteristics among many types of tumor. Collectively, these additional hallmarks are referred to as the stress phenotypes of cancers including DNA damage stress, oxidative stress, mitotic stress, proteotoxic stress, metabolic stress and immune stress. A novel hallmark of cancer RNA deregulation has been newly proposed as another hallmark of cancer within this group of stress phenotypes. However, exploiting RNA deregulation in cancer therapy is fairly unexplored. Chordia’s research focuses on RNA deregulation, a newly identified the stress phenotype of cancers.
3. The Chordia Pipeline Focuses on “RNA Deregulation”
The recent revolution in RNA research has led to the identification of novel RNA classes with unanticipated functions, new types of RNA modifications, and an unexpected widespread transcription of extragenic regions. RNA deregulation is caused by the accumulation of these abnormal RNA of any class. Based on our expanding knowledge of RNA biology, RNA deregulation has drawn much attention from the perspective of cancer therapy. However, the development of cancer therapies targeting RNA deregulation has only just begun. Small molecules that attack the RNA maturation processes and produce aberrant RNA are currently under development.
Our pipeline includes transcription inhibitors (Cyclin-dependent kinase 12, CDK12), splicing (CDC-like kinase, CLK), RNA degradation (undisclosed), and tRNA recruitment (General control nonderepressible 2, GCN2), all of which target RNA maturation processes and generate aberrant RNA leading to additional stress. We believe our drug pipeline offers innovative cancer therapy options.
Illustrated by Chordia
Our current pipeline is represented in the diagram below.
The lead asset, CTX-712(CLK inhibitor is under Phase I study.
※ Chordia grants global rights of the CTX-177 to Ono Pharmaceuticals in Dec. 2020
Chordia asset CLK inhibitor CTX-712
Orally available, selective, and a first-in-class pan-CLK inhibitor, CTX-712 is currently in phase 1 clinical trials for advanced, relapsed or refractory malignant cancers. CTX-712 dephosphorylates serine and arginine-rich (SR) proteins and induces primarily skipped exon type of splicing changes, resulting in the generation of RNA deregulation stress. In multiple preclinical models, excessive RNA deregulation stress caused cancer cell death and tumor growth inhibition. The estimated completion of the Phase 1 study is in late 2021.
-CDC-like kinase (CLK)CLK phosphorylates SR splicing factor proteins. As components of the RNA splicing machinery, SR proteins are crucial for exon recognition. The CLK family has four family members: CLK1, CLK2, CLK3, and CLK4.
-Serine/arginine-rich (SR) proteinsSR proteins usually contain an RNA recognition motif and an arginine/serine-rich (RS) domain that is required for protein-protein interactions during splicing. Several protein kinase families, including CLKs, phosphorylate SR proteins.
An essential step in gene expression, splicing is a part of the RNA maturation process by which noncoding sequences (introns) are removed and coding sequences (exons) are ligated together. Abnormalities in splicing reactions cause RNA deregulation. Splicing is catalyzed by the spliceosome that is assembled through the ordered interaction of the spliceosomal small nuclear ribonucleo proteins and numerous other splicing factors. Somatic mutations in several splicing factors in both hematological and solid cancers generate RNA deregulation, newly identified hallmark of cancer. Cancer cells need to deal with the existing RNA stress, making them more vulnerable to additional stress than normal cells.
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a critical regulator of antigen receptor signaling that is frequently activated by genetic alterations in multiple types of lymphomas. CTX-177 is a selective, small-molecule inhibitor of MALT1 at the preclinical development stage, and its manufacture and commercial rights were granted to Ono pharmaceuticals in 2020.
Chordia asset CDK12 inhibitor CRD-1835439Orally available, selective, and a first in class CDK12 inhibitor, CRD-1835439 is currently under preliminary toxicological assessment. By overloading of RNA deregulation stress through the inhibition of transcriptional elongation, CRD-1835439 produces an anti-cancer effects in multiple preclinical cancer models. Moreover, our CDK12inhibitor has the potential to become an attractive partner in combination with PARP inhibitors or chemotherapeutic agents. The phase 1 clinical study is expected to commence in late 2023.
The first step in gene expression is transcription, which involves copying a DNA sequence to make an RNA. Transcription is performed by enzymes called RNA polymerases (Pol II) that link nucleotides to form RNA strands. Transcription abnormalities cause RNA deregulation. Cancer cells that are reliant on aberrant transcription for their growth and survival present unique opportunities for therapeutic intervention.
– RNA polymerases (Pol II) and their phosphorylation
The C-terminal domain (CTD) of Pol II comprises heptapeptide Tyr(1)-Ser(2)-Pro(3)-Thr(4)-Ser(5)-Pro(6)-Ser(7) repeats and is dynamically post-translationally phosphorylated to regulate the distinct stages of transcription initiation, elongation and termination steps. Ser2 phosphorylation has the closest association with the regulation of transcription. Therefore, we focus on the kinases that carry out this modification.
-RNA transcription-regulating kinase, cyclin-dependent kinase CDK12
Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases. CDK12 regulates RNA the elongation step of RNA transcription by phosphorylation of Ser2 on the CTD. CDK12 complexes with cyclin K to promote the elongation of transcripts, such as BRCA1 and BRCA2, involved in DNA damage responses. It is expected that the inhibition of CDK12 have a synergistic effect with PARP inhibitors and chemotherapeutic reagents.
Chordia asset GCN2 inhibitor CRD-1968099CRD-1968099, an orally available, GCN2 inhibitor, is currently under preliminary toxicological assessment. CRD-1968099 shows anti-tumor effect in preclinical models by adding excess RNA deregulation stress via aberrant tRNA accumulation. Besides inducing abnormal tRNAs, our GCN2 inhibitor is expected to enhance the tumor immunity by eliminating myeloid-derived suppressor cells (MDSCs) which act to suppress T cell functions. Preclinical profiling to identify the appropriate indication is ongoing and will support the initiation of phase 1 clinical trials in 2023.
– Aberrant tRNA accumulation due to amino acid starvation
Representative nutrients, such as amino acids, are conjugated on tRNA and carried into ribosomes to synthesize proteins. Under conditions where amino acids are limited, amino acid-unconjugated tRNA (uncharged tRNA) is accumulated. In the tumor microenvironments, the abnormal vascular development results in insufficient blood supply, which is the major reason for the deprivation of nutrients like amino acids. Cells should sense and respond by utilizing GCN2 kinase to adapt to the starved condition.
– General control nonderepressible 2 (GCN2) kinase
GCN2 is a serine/threonine-protein kinase that senses amino acid deficiency through binding to uncharged tRNA. The activation of GCN2 following elevated uncharged tRNA levels enhances amino acid uptake and synthesis via phosphorylation of its substrate, EIF2α. This process supports the production of amino acid-conjugated tRNA for protein translation. The inhibition of GCN2 under amino acid starvation results in aberrant tRNA accumulation, which from our perspective, is one of the causes of RNA deregulation stress.
– GCN2 is a putative therapeutic target for immuno-oncology
GCN2 also functions as a key suppressor of anti-tumor immunity. Indeed, GCN2 deletion drives a shift in the phenotype of myeloid-derived suppressor cells (MDSC), abrogating of its suppressive function and enhancing antitumor CD8+ T cell immunity in vivo. Our CRD-1968099 is expected to enhance antitumor immunity., Targeting GCN2 by CRD-1968099 will be a successful strategy against advanced cancers by enhancing anti-tumor immunity in addition to the elevation of RNA deregulation stress from aberrant tRNA accumulation.