CLK2

Biomarkers that could be targets for novel drugs to treat glioblastoma brain tumors have been identified by investigators at Georgetown Lombardi Comprehensive Cancer Center, providing hope for a cancer that is highly lethal. Currently, the drug most often used to treat glioblastoma, temozolomide, is uniquely able to cross the blood/brain barrier to attack the tumor but resistance develops rapidly, and many patients do not survive for more than a year after diagnosis. This new finding provides early evidence that there may be a benefit in targeting specific alterations in cancer cells with newer agents once a patients tumor becomes resistant to temozolomide. The finding appeared June 22, 2022, in Science Advances. "As a field, we have struggled to deal with the short-term effectiveness of temozolomide, as many of the drugs used successfully in other cancers are disappointing when they are subsequently tested in glioblastoma clinical trials. One way to deal with this problem is to learn enough about how we can target features that help drug-resistant glioblastoma survive," says Rebecca B. Riggins, PhD, Associate Professor and Associate Director of Education and Training at Georgetown Lombardi and co-corresponding author of the study. "We focused on the details of how temozolomide damages DNA to help radiation treatments work better. Our team found that temozolomide-resistant glioblastoma relies on a protein called CLK2, and that inhibiting the activity of CLK2 could cause widespread confusion, leading to cancer cell death." The targets the researchers identified were alterations in a key structural component of both DNA and RNA, specifically in guanine, one of the four bases that comprise DNA. Modifications to guanine can ultimately have an impact on CLK2, which has been implicated in the aggressiveness of the tumor. Beyond identifying vulnerable modifications, the researchers were able to identify drugs that help stabilize RNA and could potentially slow or stop the resistance that typically develops to temozolomide. Only about 5% of patients diagnosed with glioblastoma live for five years after diagnosis and median survival is a little over a year; survival rates havent changed much since the mid-1970s. Temozolomide (Temodar) has been the standard of care since 2005 in combination with surgery and radiation. Temozolomide's targeting of guanine also impacts structures that regulate key cancer-causing genes. If these cancer-causing genes, called oncogenes, could be kept turned off, the drug might have a longer period of activity. Some of this knowledge was gleaned from studies in a neurogenerative disease, Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrigs disease. ALS has some features that are similar to glioblastoma, therefore they might also inform new strategies for glioblastoma treatment, the researchers theorized. "Some of the mechanisms underlying neurodegenerative diseases appear to be relevant to temozolomide resistance in glioblastoma," says Deanna M. Tiek, PhD, a F99/K00 fellow at the Northwestern University Feinberg School of Medicine and The Robert H. Lurie Comprehensive Cancer Center and co-corresponding author. Tiek was a PhD student in Riggins' lab when this research began. "This work demonstrates that inspiration and insight can come from places we might not have considered, and that it's so important to take a risk, do the experiment, and see if you were right or not." The investigators are now undertaking studies in small animal models, where they will test to see if the novel CLK2 inhibitor can efficiently enter the brain and shrink temozolomide-resistant glioblastoma. "We are also investigating whether other anti-cancer drugs that attack guanine and are commonly used in triple-negative breast cancer and colorectal cancer, for example, change RNA structures in a similar way, which could make CLK2 inhibition more effective in recurrent, drug-resistant forms of those cancers as well," concludes Riggins. Deanna M Tiek, Beril Erdogdu, Roham Razaghi, Lu Jin, Norah Sadowski, Carla Alamillo-Ferrer, J Robert Hogg, Bassem R Haddad, David H Drewry, Carrow I Wells, Julie E Pickett, Xiao Song, Anshika Goenka, Bo Hu, Samuel A Goldlust, William J Zuercher, Mihaela Pertea, Winston Timp, Shi-Yuan Cheng, Rebecca B. Riggins. Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas. Science Advances, 2022. doi: 10.1126/sciadv.abn3471

KANAGAWA, Japan, June 7, 2022 /PRNewswire/ -- Chordia Therapeutics Inc. ("Chordia"), a biotech company engaged in the research and development of novel therapies for cancers, today announced that it has presented the interim results from the Phase 1 clinical trial of CTX-712, a selective pan-CDC-like kinase ("CLK") inhibitor discovered by Chordia, at the 2022 Annual Meeting of the American Society of Clinical Oncology (ASCO), which was held from June 3 to June 7. A Phase 1 clinical trial of CTX-712 in solid tumors and hematological malignancies demonstrated a clinically acceptable safety profile. As for antitumor efficacy, it was observed in multiple subjects, establishing an initial Proof of Concept (POC). Dose limiting toxicities (DLTs) observed included dehydration, decreased platelet count, and hypokalemia, and the maximum tolerated dose (MTD) for twice-weekly dosing was determined to be 140 mg. Additionally, two partial responses (PRs) and two complete responses (CRs) were observed in patients with ovarian cancer and acute myeloid leukemia, respectively. A dose-dependent increase in systemic exposure was observed in pharmacokinetics (PK) analysis, and a dose-dependent increase in exon skipping of RNAs set as pharmacodynamics (PD) markers confirmed mRNA splicing modification by CTX-712. Further studies are currently underway to determine the recommended Phase 2 dosing. "It is a great honor to be involved in the first-in-human clinical trial of a new anticancer drug candidate with a novel mechanism of action," said Dr. Noboru Yamamoto, Director of the Department of Experimental Therapeutics at the National Cancer Center Hospital and Principal Investigator of the study. "Although it is still in the early stages of clinical trials, we hope that CTX-712 will become an effective treatment for patients with advanced, relapsed, or refractory malignancies in the future." ASCO abstract number: 3080 Title: A First-in-Human Phase 1 Study of CTX-712 in Patients with Advanced, Relapsed or Refractory Malignant Tumors About CTX-712 CTX-712 is a first-in-class, orally available and selective small molecule inhibitor of CDC-like kinase (CLK), a key regulator of the RNA splicing process that plays an important role in cell growth. CTX-712 inhibits the growth of various human tumor cell lines in vitro, and in addition, exhibits antitumor activity in multiple xenograft mouse models in vivo. Details of Phase 1 Clinical Trial The Phase 1 clinical trial in Japan is investigating the tolerability, safety, and pharmacokinetics (PK) of CTX-712 in patients with advanced, relapsed, or refractory malignancies. For details of the study, please refer to JapicCTI-184188. About RNA Splicing The RNA immediately after transcription is called precursor messenger RNA which contains noncoding sequences (introns) as well as coding sequences (exons) that are needed to make proteins. RNA splicing is a process to remove the introns and connect the exons to form mature mRNA, which is then translated into protein. About CDC-like Kinases (CLKs) Kinase is a general term for enzymes that catalyze the transfer of phosphate groups in biological substances, such as ATP, over to target substances that are called substrates. Over 500 protein kinases are known in humans, of which the CLK family consists of four members – CLK1, CLK2, CLK3, and CLK4, and phosphorylates serine/arginine-rich (SR) proteins as substrates. About Serine/Arginine-rich Proteins (SR Proteins) SR protein is a general term for a group of proteins with serine (S) and arginine (R)-rich SR domains, of which about 10 types have been reported in humans. The serine in the SR domain is phosphorylated by CLK kinase. The phosphorylated SR proteins bind to the exon region of the precursor mRNA and facilitate the incorporation of the bound exon into the mature mRNA during splicing. About Exon Skipping When CTX-712 inhibits CLK kinases and the SR protein dephosphorylates, a splicing change called exon skipping occurs, in which the exons fail to be incorporated into the mature mRNA. About Chordia Therapeutics Chordia was established in November 2017 at Shonan Health Innovation Park ("Shonan iPark") in Fujisawa, Kanagawa Prefecture, as a biotech company engaged in the research and development of novel therapies for cancers, with the goal of researching and developing first-in-class anti-cancer drugs and creating innovative new drugs. In addition to its leading program for CTX-712, Chordia is engaged in the research of several developments in our pipeline, including CTX-439, a CDK12 inhibitor, which is expected to be effective in cancers with specific abnormalities, as well as GCN2 inhibitors. This press release is an English translation of a Japanese-language press release. The official language of this press release is Japanese, and the Japanese version takes precedence over the English version in terms of content and interpretation. SOURCE Chordia Therapeutics Inc.

KANAGAWA, Japan, June 7, 2022 /PRNewswire/ -- Chordia Therapeutics Inc. ("Chordia"), a biotech company engaged in the research and development of novel therapies for cancers, today announced that it has presented the interim results from the Phase 1 clinical trial of CTX-712, a selective pan-CDC-like kinase ("CLK") inhibitor discovered by Chordia, at the 2022 Annual Meeting of the American Society of Clinical Oncology (ASCO), which was held from June 3 to June 7. A Phase 1 clinical trial of CTX-712 in solid tumors and hematological malignancies demonstrated a clinically acceptable safety profile. As for antitumor efficacy, it was observed in multiple subjects, establishing an initial Proof of Concept (POC). Dose limiting toxicities (DLTs) observed included dehydration, decreased platelet count, and hypokalemia, and the maximum tolerated dose (MTD) for twice-weekly dosing was determined to be 140 mg. Additionally, two partial responses (PRs) and two complete responses (CRs) were observed in patients with ovarian cancer and acute myeloid leukemia, respectively. A dose-dependent increase in systemic exposure was observed in pharmacokinetics (PK) analysis, and a dose-dependent increase in exon skipping of RNAs set as pharmacodynamics (PD) markers confirmed mRNA splicing modification by CTX-712. Further studies are currently underway to determine the recommended Phase 2 dosing. "It is a great honor to be involved in the first-in-human clinical trial of a new anticancer drug candidate with a novel mechanism of action," said Dr. Noboru Yamamoto, Director of the Department of Experimental Therapeutics at the National Cancer Center Hospital and Principal Investigator of the study. "Although it is still in the early stages of clinical trials, we hope that CTX-712 will become an effective treatment for patients with advanced, relapsed, or refractory malignancies in the future." ASCO abstract number: 3080 Title: A First-in-Human Phase 1 Study of CTX-712 in Patients with Advanced, Relapsed or Refractory Malignant Tumors About CTX-712 CTX-712 is a first-in-class, orally available and selective small molecule inhibitor of CDC-like kinase (CLK), a key regulator of the RNA splicing process that plays an important role in cell growth. CTX-712 inhibits the growth of various human tumor cell lines in vitro, and in addition, exhibits antitumor activity in multiple xenograft mouse models in vivo. Details of Phase 1 Clinical Trial The Phase 1 clinical trial in Japan is investigating the tolerability, safety, and pharmacokinetics (PK) of CTX-712 in patients with advanced, relapsed, or refractory malignancies. For details of the study, please refer to JapicCTI-184188. About RNA Splicing The RNA immediately after transcription is called precursor messenger RNA which contains noncoding sequences (introns) as well as coding sequences (exons) that are needed to make proteins. RNA splicing is a process to remove the introns and connect the exons to form mature mRNA, which is then translated into protein. About CDC-like Kinases (CLKs) Kinase is a general term for enzymes that catalyze the transfer of phosphate groups in biological substances, such as ATP, over to target substances that are called substrates. Over 500 protein kinases are known in humans, of which the CLK family consists of four members – CLK1, CLK2, CLK3, and CLK4, and phosphorylates serine/arginine-rich (SR) proteins as substrates. About Serine/Arginine-rich Proteins (SR Proteins) SR protein is a general term for a group of proteins with serine (S) and arginine (R)-rich SR domains, of which about 10 types have been reported in humans. The serine in the SR domain is phosphorylated by CLK kinase. The phosphorylated SR proteins bind to the exon region of the precursor mRNA and facilitate the incorporation of the bound exon into the mature mRNA during splicing. About Exon Skipping When CTX-712 inhibits CLK kinases and the SR protein dephosphorylates, a splicing change called exon skipping occurs, in which the exons fail to be incorporated into the mature mRNA. Important Notice In this press release, the definition of "press release" covers any oral presentation, question and answer session, and written and/or oral materials discussed or distributed by Chordia Therapeutics in connection with this press release. This press release (including the oral description and related questions and answers) is not intended to constitute, represent, or form part of any offer, invitation, or solicitation to purchase and/or acquire anything, including securities. Disclaimer Any announcements by Chordia Therapeutics, including this press release, may contain information on products derived from pharmaceutical developments, but are intended to inform the latest information related to Chordia's business, and not intended as promotions, solicitations, advertisements, or to provide medical advice. Forward-Looking Statements This press release and materials distributed in connection with this press release may contain forward-looking statements, information, beliefs, and opinions concerning our future operations, future positioning, and performance, including estimates, projections, goals, and plans. Forward-looking statements may include, but are not limited to, expressions such as "goals," "plans," "beliefs," "hopes," "continues," "expects," "intends," "assures," "will," "may," "should," "would," "could," "estimates," "projects," and/or other similar expressions, or the negative thereof. These forward-looking statements are based on assumptions concerning a number of important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements; highly influential factors that include economic conditions surrounding our global business, which include general economic conditions in Japan and the United States, competitive pressures and developments including changes in applicable laws and regulations, which include global healthcare reform, uncertainty as to our clinical success, and challenges inherent in new product development (which include regulatory decisions and their timing,) uncertainty as to the commercial success of new and existing products manufacturing difficulties, delays fluctuations in interest rates and exchange rates claims or concerns regarding the safety or efficacy of commercial products or product candidates the impact of a health crisis, such as the COVID-19 pandemic, on Chordia and its customers and suppliers (including foreign governments in countries in which the Company conducts business) or other aspects of its business. We undertake no obligation to update any forward-looking statements contained in this press release or any other forward-looking statements we may make, except as required by law or stock exchange rules. Past performance is not indicative of future operating results, and any of our operating results or statements in this press release are not estimates, forecasts, warranties, or projections of our future operating results. About Chordia Therapeutics Chordia was established in November 2017 at Shonan Health Innovation Park ("Shonan iPark") in Fujisawa, Kanagawa Prefecture, as a biotech company engaged in the research and development of novel therapies for cancers, with the goal of researching and developing first-in-class anti-cancer drugs and creating innovative new drugs. In addition to its leading program for CTX-712, Chordia is engaged in the research of several developments in our pipeline, including CTX-439, a CDK12 inhibitor, which is expected to be effective in cancers with specific abnormalities, as well as GCN2 inhibitors. This press release is an English translation of a Japanese-language press release. The official language of this press release is Japanese, and the Japanese version takes precedence over the English version in terms of content and interpretation. View original content: SOURCE Chordia Therapeutics Inc.