THZ-1

Exscientia is aiming to publish monotherapy dose escalation date this year. Exscientia has taken full ownership of its oral CDK7 inhibitor candidate, buying out partner GT Apeiron for $20 million. The AI-enabled biotech plans to advance the molecule into a breast cancer combination trial. GT Healthcare, an investor in Exscientia, launched GT Apeiron in 2019 and immediately signed a deal to fund the discovery of cancer drugs with the AI specialist. Exscientia and GT Apeiron terminated the first deal in 2021 and entered into a joint operation and cost sharing arrangement for the development and commercialization of multiple programs. The partners began a phase 1/2 clinical trial of the lead candidate, the oral CDK7 inhibitor GTAEXS617, in July 2023. Now, Exscientia has bought out its partner. GT Apeiron last disclosed funding when it raised a $17.5 million series A round in March 2022.  Exscientia is paying $10 million in upfront cash and a further $10 million in upfront equity to take control of the program and ownership of all intellectual property. GT Apeiron will receive single-digit royalties if GTAEXS617 comes to market. Exscientia will take on all existing development costs but still expects its runway to extend well into 2027. The arrangement gives Exscientia full ownership of an asset it believes can address the limitations that have held CDK7 inhibitors back to date. Eli Lilly took a CDK7 inhibitor into human testing in 2019 but stopped the trial over a lack of efficacy. Syros Pharmaceuticals dropped one asset, SY-1365, and another, SY-5609, is on the backburner. Carrick Therapeutics has pushed its prospect, samuraciclib, into phase 2.  Exscientia discussed the positioning of GTAEXS617 on an earnings call in May, telling investors that, while it expects to see some level of monotherapy activity, combinations will be the focus for clinical use. Toxicity is the barrier to combinations, including with immunotherapies. Ben Taylor, Exscientia’s chief financial and strategy officer, discussed why GTAEXS617 may be free from problems that affect some rival molecules.  “It was specially designed to get around an issue that a number of the other competitive molecules have, which is being a transporter substrate. We think we've got a really nice advantage there and hopefully you'll be able to see that in the data,” Taylor said. “Because if we can get a nice safe profile, this is a mechanism that clearly should work, and there's a number of different combination opportunities for it.” Exscientia is aiming to publish monotherapy dose escalation data this year. If all goes to plan, the biotech will start a dose escalation study combining GTAEXS617 with a selective estrogen receptor degrader in breast cancer around the end of the year.

Blocking a protein known as CDK7 could prevent heart damage associated with a commonly used cancer chemotherapy medication, according to a new study. Importantly, the researchers also found that inhibiting CDK7 could help enhance the medication's cancer-killing capability. Based on an animal model, the study findings could provide a foundation for future treatment strategies to reduce chemotherapy-related heart toxicity and increase treatment effectiveness. This could ultimately help increase the lifespan of people with cancer. Blocking a protein known as CDK7 could prevent heart damage associated with a commonly used cancer chemotherapy medication, according to a study led by scientists at Washington State University. Importantly, the researchers also found that inhibiting CDK7 could help enhance the medication's cancer-killing capability. Based on an animal model, the study findings could provide a foundation for future treatment strategies to reduce chemotherapy-related heart toxicity and increase treatment effectiveness. This could ultimately help increase the lifespan of people with cancer. Heart damage related to chemotherapy treatment can surface decades after treatment and can result in heart attacks, heart failure, cardiomyopathy and other types of heart disease. Published in the journal Cardiovascular Research, the WSU study focused on doxorubicin, a chemotherapy drug used to treat breast cancer, lymphoma, leukemia and other cancers. Capable of killing a wide range of cancer cells, doxorubicin and other similar chemotherapy medications are known to be toxic to the heart. Despite this toxicity, the drug still sees a lot of use. "Doxorubicin remains the mainstay treatment for certain cancer types for which targeted therapies or other better treatments are not available," said senior study author Zhaokang Cheng, an associate professor in the WSU College of Pharmacy and Pharmaceutical Sciences. Cheng has been working to unravel the underlying mechanisms of doxorubicin-induced heart toxicity to make the use of doxorubicin safer for patients who rely on the drug. This new study builds on findings from earlier research that showed that doxorubicin activates a protein known as CDK2. That protein then activates another known as FOXO1, which causes heart cells to die. Cheng's team collaborated with WSU cancer biology researcher Boyang (Jason) Wu to take a closer look at CDK7, a protein that helps fuel cell growth and has been shown to play a role in the development of cancer. The researchers found that CDK7 activated CDK2, which set off the chain of molecular signals that eventually led to heart cell death. They also showed that mice that lacked the CDK7 gene were protected from doxorubicin-induced heart toxicity. Next, they used a CDK7 inhibitor drug known as THZ1 to block the protein's activity and examine the impact on heart health and cancer growth. A similar inhibitor is currently being tested as an anticancer drug in clinical trials, but its effect on the heart is still not clear. "We are the first to study the effect of THZ1 on the heart and on tumor growth in the same model," said study first author Jingrui Chen, a WSU research associate. "And what we found is that this CDK7 inhibitor drug can increase heart function and at the same time inhibit tumor growth." Though more research is needed, the researchers said their findings suggest that combining doxorubicin and THZ1 could help prevent heart damage and increase the effectiveness of chemotherapy treatment. The researchers' next step is to test the effect of THZ1 on heart damage and cancer growth in younger mice and follow them longer. This would more closely mimic long-term doxorubicin-induced heart toxicity seen in childhood cancer survivors. They also plan to look at other proteins that may somehow be involved in the signaling pathway that underlies doxorubicin-related heart damage. Primary funding support for the study came from the National Heart, Lung and Blood Institute -- a component of the National Institutes of Health -- with additional support from the National Cancer Institute.