Synthetic lethal' emerging target - PRMT5 development geometry?

Arginine methylation, a type of histone methylation, is one of the most common post-translational modifications in mammals, mainly regulated by the PRMT gene family.

In mammals, there are a total of 9 PRMTs, divided into three types: I, II, and III. Type I includes PRMT1, 2, 3, 4, 6, 8, which mainly catalyzes the formation of monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA); Type II. includes PRMT5 and 9, which mainly catalyze the formation of MMA and symmetric dimethylarginine (SDMA); Type III includes PRMT7, which mainly catalyzes the formation of MMA.

Studies have shown that alterations, mutations or deletions in the enzyme activity of PRMTs often induce the initiation, development or metastasis of cancer. Among the many PRMTs, PRMT5 has been relatively studied in recent years and has attracted the highest attention. As an epigenetic enzyme, PRMT5 is most eye-catching and "synthetically lethal" mechanism.

The so-called synthetic lethality means that for two genes in the cell, either of them mutates alone or does not function, it will not cause cell death; When the two are mutated or cannot be expressed at the same time, it will lead to cell death, and the principle can be used to selectively kill tumor cells without affecting normal somatic cells.

In 2016, two articles published in Science first reported the "synthetic-lethal" effect of inhibiting PRMT5 in MTAP-deficient tumors. The synthetic lethal gene that constitutes PRMT5 is methyl thiadenosine phosphorylase (MTAP), a tumor suppressor gene that is often missing in tumors. Patients with MTAP deletion account for about 15% of all solid tumors, including about 15% of NSCLC, 28% of esophageal cancers, 26% of bladder cancers, and 10% of esophageal and gastric cancers.

In addition to synthetic lethal effects, PRMT5 is involved in DNA repair, cell cycle, transcriptional regulation through methylation modification of the substrate arginine, and has a crucial impact on various cell functions. At present, the research on PRMT5 small molecule inhibitors has become a hot spot in the research and development of anti-tumor drugs. Let's take a look at what the corporate layout is.

PRMT5 domestic and foreign layout

There are currently about thirty PRMT5 inhibitors in development, of which about half are in clinical stages. The fastest progressing is GSK3326595, jointly developed by Epizyme and GlaxoSmithKline (GSK), which is currently the only PRMT5 inhibitor to enter phase II clinical trials.

In addition, Amgen's AMG193, MiratiTherapeutics' MRTX1719, SKLifeScience's SKL27969, and Tango Therapeutics' TNG908 have completed Phase I clinical trials.

Progress in PRMT5 inhibitor development

GSK3326595

GSK3326595 is a selective small molecule inhibitor of PRMT5 and is a non-competitive inhibitor. It carries a tetrahydroisoquinoline fragment (THIQ) that forms a potential π-π accumulation effect with PRMT5's unique residue Phe327, which effectively inhibits tumor volume. GSK3326595 has good brain permeability and anti-tumor effect.

Currently, two clinical trials are evaluating GSK3326595. In the first trial, 54 patients with tumors were enrolled, including adenoid cystic carcinoma, colorectal cancer and breast cancer. Results showed that 89% of patients experienced treatment-related adverse events, the most common of which included fatigue, anemia, nausea, hair loss, and mood disorders.

Another phase I/II safety and clinical activity trial for relapsed and/or refractory myelodysplastic syndrome (MDS), chronic myelomonocytes leukemia (CMML), and low-proliferative AML due to MDS is ongoing.

AMG193

AMG193 is a PRMT5 inhibitor developed by Amgen. In July 2022, Amgen entered into a clinical trial collaboration and supply agreement with IDEAYABiosciences to evaluate the efficacy and safety of the synthetic-lethal combination of the MAT2A small molecule inhibitor IDE397 and AMG193 in MTAP-deficient solid tumors.

Currently, Amgen is conducting a randomized, open-label Phase I/IB/II trial overseas to evaluate the safety, tolerability, pharmacokinetics and efficacy of AMG193 alone or in combination with docetaxel in patients with advanced solid tumors with MTAP deficiency.

MRTX1719

MRTX1719 is a PRMT5 inhibitor developed by MiratiTherapeutics, which has been proved to be highly selective for PRMT5 in vitro tests, and can use a synthetic lethal mechanism to selectively inhibit MTAP-deficient cells without affecting normal cells.

Mirati has conducted a Phase I/II, multicenter clinical study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of MRTX1719 in patients with advanced, unresectable or metastatic solid tumors with homozygous deletion of the MTAP gene.

TNG908

TNG-908 is a PRMT5 inhibitor developed by Tango Therapeutics and approved for IND in the United States in January 2022.

Preclinical studies have shown that TNG-908 has strong selectivity for MTAP-deficient tumors and has a powerful anti-tumor effect in vitro and in vivo. Tango Therapeutics expects to provide preliminary safety and efficacy data for TNG-908 in the first half of 2023.

SCR-6920

SCR-6920 is a PRMT5 inhibitor developed by Simcere Pharmaceutical, which has high inhibitory activity and high selectivity for PRMT5.

Pharmacokinetic studies have shown that SCR-6920 tends to be distributed in tumors, and the ratio of intratumor drug concentration to plasma drug concentration is about 10 times that of other PRMT5 inhibitors under investigation, which means that SCR-6920 has lower plasma exposure while obtaining better tumor inhibition effect, which can reduce target-related hematotoxicity to a greater extent.

In March 2022, a multicenter Phase I clinical study of SCR-6920 for the treatment of advanced malignancies was approved by CDE for clinical trials to evaluate the safety, tolerability, efficacy, and pharmacokinetic profile of SCR-6920.

SH3765

SH3765 is a PRMT5 inhibitor independently developed by Shenghe Pharmaceutical with global independent intellectual property rights. In May 2021, SH3765 was approved by CDE for clinical trial and is intended to be used for the treatment of advanced malignant tumors, including but not limited to solid tumors and non-Hodgkin lymphoma. Previously, SH3765 received FDA clinical trial approval in February 2021.

SYHX2001

SYHX2001 is a PRMT5 inhibitor developed by CSPC Pharmaceutical Group. In December 2021, SYHX2001 was approved by CDE for clinical trials for the treatment of advanced solid tumors and relapsed and refractory hematological tumors.

Preclinical studies have shown that SYHX2001 has significant efficacy in acute myeloid leukemia, pancreatic cancer, melanoma and adenoid cystic carcinoma, and has good safety and pharmacokinetic characteristics, which is of great clinical development value.

As an emerging class of anti-tumor drugs, PRMT5 inhibitors are still in the early stage of clinical development, and PRMT5 inhibitors are also promising "synthetic lethal" therapy drugs after PARP inhibitors, showing broad therapeutic prospects in solid tumors and hematological tumors. At present, no such drugs have been approved for marketing at home and abroad, which is a challenging and promising track.