STM-2457

A new class of compounds currently in development against acute myeloid leukemia has been discovered to block coronavirus reproduction in human lung cells. In order to reproduce in the body, viruses must hijack some of the natural genetic mechanisms to assist. Coronaviruses encode a complete set of genetic instructions in RNA chains. This led researchers to question whether modifying enzymes would be able to alter the production of viral proteins that enable virus multiplication. A research team at NYU Grossman School of Medicine found that the reproduction of SARS-CoV-2 and HCoV-OC43, the less severe, seasonal coronavirus that causes the common cold, requires the action of the human enzyme METTL3. METTL3 installs the m6A methylation on RNA, a modification instruction in the genetic instructions for both coronaviruses studied. This discovery led them to the next step – would inhibiting the action of METTL3 hinder the reproduction of the viruses? In steps Storm Therapeutics. A spin-out from the University of Cambridge, Storm co-founder Tony Kouzarides worked off the findings showing the role of METTL3 in both establishing disease and leukemia cell differentiation. Kouzarides team published a paper in April showing the efficacy of a catalytic METTL3 inhibitor in mouse models of AML. Storm’s candidate, STM2457, decreased AML engraftment and increased survival. The drug is expected to enter the clinic early next year. The NYU Langone team had other ideas for STM2457. Partnered with Storm, STM2457 was tested alongside an inactive control compound on cultures of human lung cells infected with either seasonal “common cold” coronavirus or SARS-CoV-2. Using imaging to track viral infection on thousands of cells, the cells treated with the highest dose of STM2457 were the proof in the pudding. Cells infected with HCoV-OC43 reduced by more than 80%. Even more encouraging, SARS-CoV-2 reproduction dropped by more than 90% compared to the inactive compound. "Our results represent the first time a chemical inhibitor of METTL3 has been shown to have an anti-viral effect for coronaviruses, or any virus," says senior study author Ian Mohr, Ph.D., professor in the Department of Microbiology at NYU Langone Health. "This represents a necessary step in drug development, identifies new targets, and reveals an unexpected strategy to halt the coronavirus lifecycle." The team intends to further investigate the mechanism of m6A modification and its influence on the virus and host gene expression in cells infected with coronaviruses. The next step will be determining if STM2457 can prevent severe disease in animals. "We went into it hoping to learn about the differences between the biology of innocuous and pandemic coronavirus infections," says co-corresponding author Angus Wilson, Ph.D., associate professor in the Department of Microbiology at NYU Langone Health. "If anything we found that both share a dependence upon the m6A methylation machinery. That creates the hope that inhibiting METTL3 may also be useful against future pandemic coronaviruses."

University of Cambridge researchers published the first preclinical validation for a novel therapeutic strategy targeting epitranscriptomic modifiers of RNA, opening the door for spinout STORM Therapeutics’ acute myeloid leukemia therapy (AML)–and potentially much more. Tony Kouzarides, cofounder and director of Milner Therapeutics Institute at Cambridge and a Storm co-founder, led the team that published the paper in Nature in April, which was the first published data showing the efficacy of a catalytic METTL3 inhibitor in mouse models of AML. Consistent with earlier findings on METTL3’s role in regulating disease, Storm’s STM2457 decreased AML engraftment and increased survival. Last year the company nominated a related compound as its lead clinical candidate, and Kouzarides said Storm expects it will reach clinical testing early next year. This is the first published in vivo data for a small molecule inhibiting an epitranscriptomic disease target, but the approach has been brewing for years. Just as epigenetic modifications to DNA can directly control gene expression, epitranscriptomic modifications control RNA gene expression indirectly via RNA translation, making them potential therapeutic targets. While the first epigenetic therapy was approved in 2004, the connection between epitranscriptomic modifiers and disease pathways have only begun to be characterized. METTL3 is an epigenetic writer of N6-methyladenosine (m6A) modifications, the most prevalent reversable epitranscriptomic modification in human cells. METTL3 and other writers form m6A modifications via methylation of certain RNA sequences, which is key for numerous processes in normal cells. This would seem to make it an unlikely therapeutic target. But in 2017, two key publications began to elucidate the role of m6A in AML and demonstrate the possibility of targeting the pathway without toxicity in healthy cells. Kouzarides and colleagues published findings showing the role of METTL3 in both establishing disease and in leukemia cell differentiation. Separately, a team from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center showed in a Nature Medicine paper that leukemia cells were more dependent on METTL3 than normal hematopoietic cells. Samie Jaffrey, an author on the paper and a professor of pharmacology at Weill Cornell, said that the abnormal differentiation seen in leukemia cells was abrogated by only mild inhibition of METTL3–important because a complete METTL3 inhibitor delivered systemically would be highly toxic. The new paper from the Cambridge researchers was therefore a proof-of-concept for Jaffrey’s approach as well. “I think a lot of other people were cautious because they felt it was a fool’s errand to go after METTL3,” he said. “I think this makes the METTL3 target seem much more validated.” Researchers from both groups founded companies to exploit the therapeutic pathway in leukemia. Kouzarides and fellow Cambridge professor Eric Miska co-founded Storm Therapeutics in 2015 to develop first-in-class therapies against RNA epigenetic targets. Jaffrey co-founded Gotham Therapeutics in 2017. Storm has raised £42 million ($59.4 million) seed and Series A rounds, while Gotham raised $54 million in a Series A. At least one other company appears to be chasing METTL3: Accent Therapeutics, which last year raised a $63 million B round and announced a co-development deal with AstraZeneca utilizing its RNA-modifying protein platform, has presented in vitro data in AML for its inhibitors of METTL3 and METTL14, another m6A writer. Additional publications have shown more therapeutic possibilities for targeting the m6A pathway, suggesting it may be possible to increase sensitivity to existing therapies in pancreatic and ovarian cancer, for example. m6A methylation has also been linked to a suppressed immune response in infectious diseases like Zika and HIV, and in April a team led by University of California San Diego School of Medicine professor Tariq Rana published in vitro data showing METTL3 inhibition could suppress SARS-CoV-2 replication. Rana’s team has previously shown that the inhibition of ALKBH5, an m6A eraser, can improve the efficacy of cancer immunotherapies in mice, and Rana has spun out ViRx Pharmaceuticals with plans to license intellectual property from the university around RNA therapeutics for broad-spectrum antivirals. But Storm, Accent and Gotham are starting in AML for a reason. Optimizing compounds for AML is an easier task because unlike other cancers, “when you inhibit the METTL3 pathway, you can see the cells differentiating with your eyes,” Jaffrey said. “In most cancers, you can inhibit METTL3 and they will die but you’re inhibiting it to such a degree that probably normal cells will die too. it all comes down to one thing: therapeutic index.” Gotham has identified several solid tumor types with comparable “m6A addictions” it is looking at closely, he added. Several other companies are likely targeting different epitranscriptomic targets. Academic work by an Accent scientific cofounder, Chuan He, has focused on YTHDF1, an RNA reader that could function as an immune system control switch for modulating the response to cancer immunotherapy. He is also a chemistry professor at the University of Chicago. Accent is also pursuing ADAR1 inhibitors for cancer. Silicon Therapeutics, which uses a physics-based approach to drug design for intractable protein targets, is developing an ADAR1 antagonist for cancer. The company said inhibiting ADAR1 can both activate innate antitumor immune cells and directly kill tumors. Gotham is also looking into additional epitranscriptomic regulators that are much less prevalent than m6A, Jaffrey says, using its screening platform to identify and analyze RNA modifiers. Kouzarides envisions a lot more opportunities ahead for the burgeoning space. “These enzymes can potentially regulate many different processes in many different diseases,” he said. He declined to specify which other epitranscriptomic targets Storm is chasing, but the company is currently raising a Series B round to support its anticipated clinical testing for a METTL3 inhibitor in 2022.