On July 17, 2024 Anagenex, a pioneering drug discovery company pairing large-scale data generation with proprietary artificial intelligence (AI) to discover the next generation of small molecule medicines, reported the company has nominated PRMT5 and MAT2A as its first two preclinical programs (Press release, Anagenex, JUL 17, 2024, View Source [SID1234644943]). PRMT5 is an essential gene required for cell survival. Inhibition of the metabolic protein MAT2A leads to PRMT5 inhibition. Both of these proteins are viewed as potential cancer therapeutic targets.
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Anagenex has built a platform that pairs large-scale data generation enabled by artificial intelligence (AI) to find and develop hits to multiple targets simultaneously, exploring entire pathways to identify the most promising compounds to modify disease biology.
Anagenex prioritizes targets with clear human validation. Targets with a human biomarker are four times more likely to be approved, however hundreds remain un-drugged because these often belong to novel target classes or challenging mechanisms. Synthetic lethal oncology, a situation in which loss of function of two genes together result in cell death, while loss of either gene alone does not, is a particularly fruitful area for targets because they often come with an associated human biomarker and massive unmet medical need persists.
Anagenex’s first programs addressing PRMT5 and MAT2A fit this validated human target hypothesis. PRMT5 is a pan-essential gene and MAT2A inhibition leads to inhibition of PRMT5. Both leverage MTAP deletion, a gene that is lost in 15% of all solid tumors, providing a unique mechanism to target therapies exclusively to tumors. While competitive programs are showing value in the clinic, Anagenex’s unique platform has been able to identify highly novel compounds for these targets which it believes will help patients by increasing selectivity and brain penetrance.
"Today none of the programs in the clinic have been able to unlock the majority of patients who might be eligible for PRMT5 and MAT2A inhibitors," said Ryan Kruger, Chief Scientific Officer of Anagenex. "PRMT5 needs to be hit extremely effectively but hitting PRMT5 in normal tissue creates dose-limiting side-effects. MTAP loss provides us with a magic bullet to inhibit PRMT5 only in tumor cells either through the inhibition of MAT2A or through inhibition of PRMT5 directly."
The most effective PRMT5 compounds in the clinic are 74-fold selective for tumors over regular cells, but preclinical and clinical data suggests that at least 250-fold selectivity is needed to provide treatment benefit to most patients. Brain penetrance is also important because 40% of patients in the primary indication, Non-Small Cell Lung Carcinoma (NSCLC), experience progression to brain metastases that are often fatal.
Anagenex has developed a series of scaffolds with extreme selectivity, and preliminary work is demonstrating that some of those are brain penetrant. Anagenex is targeting to nominate one of these programs as a development candidate in 2H 2025.
"Essentially all of the competitive compounds targeting PRMT5 and MAT2A are exploring the same scaffolds," stated Kruger. "Simply rehashing chemistry others have explored won’t generate the breakthroughs patients need. Fortunately, our platform has discovered several scaffolds that are completely unrelated to those currently being clinically evaluated, giving us a fresh endeavor to help patients in a whole range of cancers."
In parallel to the announcement of the targets within Anagenex’s synthetic lethal oncology portfolio, the Company is planning to expand into immunology in 2024, leveraging its unique discovery platform to solve the most challenging immune disorders. This follows Anagenex’s initiation of a partnership with Nimbus Therapeutics across a variety of targets, which was previously announced in late-2023.
"Our platform is uniquely suited to finding chemical matter for any target, fulfilling our mission to find a molecule for every malady," said Nicolas Tilmans, Anagenex CEO. "The true power of our platform is in the scalability, and its capability to screen many targets in parallel, then investigate them with up to 100 million target-focused compounds. This scale of early-stage compound investigation ensures that we will generate multiple compounds that will make it to the clinic."