Amgen Discloses AMG 193, an MTA-Cooperative PRMT5 Inhibitor in Phase 1/2 Clinical Trials for MTAP-Deleted Cancers

Jun 23, 2025 06:30 CST Updated 06:30

Amgen

Developer of Treatment Drugs for Serious Diseases

DOI: 10.1021/acs.jmedchem.4c03121

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AMG 193It is an MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deficient cancers, with 5 ongoing clinical studies, including 2 Phase I, 1 Phase II, and 2 Phase I/II trials.

Methylthioadenosine phosphorylase (MTAP), located near the tumor suppressor gene CDKN2A, is deleted in 10-15% of human cancers. The loss of MTAP leads to the accumulation of methylthioadenosine (MTA), which structurally resembles S-adenosylmethionine (SAM), the methyl donor for the essential cellular protein arginine methyltransferase 5 (PRMT5).

Therefore, MTA partially inhibits PRMT5 by competing with SAM, making MTAP-deficient tumors more susceptible to further PRMT5 inhibition.

AmgenRecently, through a series of reports, utilizing cofactor-directedDNA Encoded Library (DEL)Screening technology has led to the discovery of MTA-cooperative PRMT5 inhibitors, which have been further optimized and developed.Clinical Candidate Compound AMG 193。

Recently (Mar. 27), regardingAMG 193 The final optimization and characterization results were published in J. Med. Chem. Up.

1. Timeline of Amgen-related reports

Summary of AMG 193 Related Reports

February 2022AMG 193 has officially entered clinical recruitment for the treatment of MTAP-deficient cancers by targeting PRMT5 inhibition.

September 16, 2024, Amgen collaborates with multiple institutions in Annal. Oncol. Published an article, disclosing the results of Phase I clinical trials.

DOI：10.1016/j.annonc.2024.08.2339

Phase I trial results indicate that AMG 193 demonstrates good safety, with no clinically significant myelosuppression, and anti-tumor activity has been observed in various MTAP-deleted solid tumors.

January 13, 2025, Amgen in AACR JournalCancer Discovery The structure of AMG 193, its potency in MTAP-deficient cancer cells, and its antitumor activity in human cell lines and patient-derived xenograft models were disclosed.

DOI: 10.1158/2159-8290.CD-24-0887

At the same time, it briefly introduced the short history of AMG 193 from Hit to Lead, and then optimized to Clinical Candidate.

March 18, 2025, Amgen inJ. Med. Chem.Published an article introducing the discovery of DEL Hit AM-9959, and the important findings from structure-based SAR optimization to AM-9934 and AM-9747. Through in vitro/in vivo characterization, a key lead compound with oral potential was identified.

DOI：10.1021/acs.jmedchem.4c03101

The focus of this article is on the structure-based optimization process and optimization strategies. Previous related sharing has provided detailed analysis, see the comment section or related sharing at the end of the article.

March 27, 2025, Amgen again in J. Med. Chem. The process of optimizing lead compounds to obtain the clinical candidate AMG 193 is disclosed in detail, along with the characterization of its biological activity, in vivo/in vitro efficacy, drug metabolism, pharmacokinetic properties, and the progress of its preclinical and clinical studies.

DOI: 10.1021/acs.jmedchem.4c03121

This article is also the focus of this sharing.

May 16, 2025, Amgen inPNASReported onCofactor-Assisted DNA-Encoded Library ScreeningThe dual-track setup method can directly identify the binding compounds of the target mechanism from DEL screening, which has high guiding significance for the expansion of DEL screening and application, and can directionally discover inhibitors with specific mechanisms.

DOI：10.1073/pnas.2425052122

This article was shared yesterday. See the comment section or related past shares.

2. Core Issues of the Study

Clinical Significance of MTAP Deletion

MTAP (Methylthioadenosine Phosphorylase)Occurs in 10-15% of human cancers (such as glioblastoma, pancreatic cancer), often due to the deletion of the chromosome 9p21 locus adjacent to the tumor suppressor gene CDKN2A.

MTAP deletion leads toMTA (Methylthioadenosine)Accumulation, MTA andSAM (S-adenosylmethionine)Structurally similar, as shown in Figure A below, and SAM is easily degraded to MTA.

PRMT5 is a type II arginine methyltransferase dependent on the cofactor methylosome protein 50 (MEP50), catalyzing the methylation and dimethylation of protein arginine residues as shown in the figure above, whereSAM as a methyl donor。

MTAP deletion leads to a reduction in physiological concentration, causing MTA accumulation, which selectively competes with SAM for binding to PRMT5 and inhibits its enzymatic activity.`, making MTAP-deficient tumors more sensitive to PRMT5 inhibition,`Forming a "synthetic lethality" effect。

Current Status and Challenges of PRMT5 Inhibitors

As shown in the figure below, the first generation of clinical PRMT5 inhibitors (such asGSK3326595、JNJ-64619178、PF-06939999), forNon-selectively target the MTA-bound form of PRMT5, can inhibit PRMT5 in both MTAP-deficient and normal cell nuclei.

Therefore, the first-generation PRMT5 inhibitors have severe toxicity to normal tissues, such as pancytopenia, infertility, and cardiac hypertrophy.

To overcome toxicity, it is necessary to develop novel PRMT5 inhibitors that preferentially target PRMT5 in MTAP-deleted tumors while sparing PRMT5 in normal tissues, which is expected to reduce toxicity and improve the therapeutic index, potentially enhancing the therapeutic potential of PRMT5 inhibition.

This innovative inhibitor isInhibitors Selectively Targeting the PRMT5·MTA Complex, avoiding normal cytotoxicity.

As shown in the figure above, major companies have successively disclosed new-generation MTA-collaborative PRMT5 inhibitors, as shown in the figure above.Compounds 8-12 and 31, among whichCompounds 8, 9A, 9B, 31During 2022-2023, they entered the clinical stage respectively.

Among them, Amgen discovered MTA-cooperative PRMT5 inhibitors through DEL screening and optimized from DEL Hit step by step to finally obtain the clinical candidate molecule AMG 193.

3. Discovery and Characterization of AMG 193

Optimization of Lead Compounds

Basic Properties of the Lead Compound AM-9747

AM-9747 was discovered and optimized as a lead compound from DEL Hit. Its ADME property analysis shows high permeability and low to moderate turnover in both human and mouse liver microsomes.

After administration of 1 mg/kg, the clearance of AM-9747 was 2.3 L/h/kg; the volume of distribution was 2.3 L/kg, and the half-life was 2.3 h. The bioavailability (%F) was 23%.

In addition, AM-9747 exhibited time-dependent inhibition (TDI) of CYP3A4, with an inhibition rate of 60%.

Therefore, starting with the AM-9747 lead compound,Continued Optimization GoalsAs follows:

(1) Maintain its high efficiency as an inhibitor of the PRMT5-MTA complex and selectivity (MTAP-deficient vs wild-type cells);

(2) Improve pharmacokinetics (including oral bioavailability and brain permeability); enhance its ADME (absorption, distribution, metabolism, excretion) properties;

(3) Reduce the risk of drug-drug interactions (DDI), including time-dependent inhibition (TDI) of the CYP3A4 enzyme and activation of human PXR (pregnane X receptor).

Structure-Based Research and Optimization Guidance

As shown in the figure below, the binding of the lead compound AM-9747 to the X-ray crystal structure of the PRMT5-MTA complex is displayed.

From the above crystal structure, it can be observed that AM-9747 interacts with several binding pockets.Key Interactions：

(1) Anchoring effect of the 2-aminoquinoline core pharmacophore：

On the one hand, through C2 amino and quinoline N The motif forms a salt bridge bidentate interaction with the E444 side chain; on the other hand, it enhances cooperativity through van der Waals contacts between the quinoline ring C2 amino group, C3 methyl group, and the MTA sulfur atom.

(2) π-π Stacking and Hydrophobic Interactions

As shown in Figure B above, including the quinoline ring and W579/F327Double-ring π-π stacking;Trifluoromethylpyridyl andF580π-π stacking, itsCF₃ GroupEmbedded byY304/A301/V326The formed hydrophobic pocket; pyrimidine base withL312/Q309π-π interactions.

(3) Hydrogen Bond Network Interactions

Including, amide carbonyl withF580 Main Chain-NHHydrogen bonding; Pyridine nitrogen atom throughWater Molecular BridgeAndQ309 Side Chain CarbonylForming a hydrogen bond network.

（4）Structural Basis of MTA Synergy

AM-9747 binds toPeptide Substrate Pocket, with E435 main chain carbonylHydrogen bonding forces the E435 side chain to turn towards the MTA binding pocket, interacting withK333/Y334 Form a polar network (maintaining MTA-binding conformation), blocking the conformational rotation required for the E435 side chain to enter SAM binding, thereby selectively stabilizing the PRMT5·MTA complex.

In summary, based on the binding position of AM-9747 in the PRMT5-MTA complex, further optimizable directions are suggested:

(1) Substitution at the C4 position of quinoline;

(2) The opportunity to introduce heteroatoms into the bicyclic core;

(3) and the exploration space of the N,N-dialkyl region of the central amide group.

AM-9747 Metabolite ResearchIndicates that the main metabolites are derived from the oxidation of the 3-methylquinoline ring system (12 A), while the formation of N-oxide 12 B and glucuronide 12 C is minimal.

Therefore, in order to reduce the oxidative conversion of AM-9747, the research team attempted to replace the 3-methylquinoline with an ether heterocycle while keeping the left-hand side (LHS) structure unchanged, and modified the right-hand side (RHS) as shown in the figure below.

Among them,3-MethylquinolineReplace withDihydrofuran tricyclic system(such as compounds17-21), significantly reduce CYP3A4 time-dependent inhibition (TDI < 10%), and improve metabolic stability.

LHS Optimization：

Introduction(S)-3-(4-Trifluoromethylphenyl)morpholine(Compound31), reducing the efflux ratio (ER = 3), and improving oral bioavailability (77% in mice, 100% in dogs)

FinalizedAMG 193 (Compound 31)The final candidate molecule is a tricyclic amide structure that binds to the PRMT5·MTA complex (as shown in the figure below) and is stabilized through hydrogen bonds (E444, E435), π-π stacking (W579, F327), and van der Waals forces.

Preclinical Highlights Data

In Vitro Activity and Selectivity: The IC50 of AMG 193 for the proliferation inhibition of HCT116 MTAP-deficient cells is 0.107 μM, and the IC50 for wild-type cells is 4.33 μM, with a selectivity of approximately 40-fold; it also has potent inhibitory effects on endogenous MTAP-deficient tumor cells such as BxPC-3, U87MG, and DOHH-2.

In Vivo Efficacy：

In the HCT116 MTAP-deficient mouse xenograft model, 100 mg/kg QD oral administration resulted in 87% tumor growth inhibition (TGI); in the BxPC-3 pancreatic cancer and U87MG glioblastoma models, TGI reached 96% and 88%, respectively.

Pharmacokinetics and Safety：

AMG 193 exhibits low clearance, moderate distribution volume, and long half-life in mice, rats, and dogs, with high oral bioavailability and good solubility across multiple species. It has no hERG binding risk, weak inhibitory effects on cytochrome P450 enzymes such as CYP3A4, 2D6, and 2C9, and low risks of TDI and hPXR activation.

4. AMG 193 and Its Analog Synthesis

5. Summary and Outlook

This article provides a detailed report on the discovery process of AMG 193, including its chemical optimization, biological activity, in vivo and in vitro efficacy, pharmacokinetic properties, as well as the results of preclinical and clinical studies.

AMG 193, as an MTA-cooperative PRMT5 inhibitor, demonstrates significant therapeutic potential for MTAP-deficient cancers, while exhibiting favorable pharmacokinetic properties and a low risk of drug interactions.

Currently, AMG 193 is undergoing clinical trials to evaluate its safety and efficacy in patients with advanced MTAP-deleted solid tumors.

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