PRMT5

AMG 193 is a second-generation protein arginine methyltransferase 5 (PRMT5) inhibitor that targets the MTA-bound state of PRMT5 in methylthioadenosine phosphorylase (MTAP)-null tumors. PRMT5 is responsible for methylation and gene silencing of cell-essential proteins dysregulated in cancer and is partially inhibited in tumors harboring MTAP deletion, which occurs in ~15% of solid tumors[2].

First generation PRMT5 inhibitors were intolerable due to indiscriminate inhibition of PRMT5 leading to dose-limiting myelosuppression. In preclinical studies, AMG 193 demonstrated selective antitumor activity in MTAP-null models by further suppressing PRMT5 function while sparing normal function, thereby improving upon first generation molecules. We report the initial clinical results from dose-escalation in the ongoing first-in-human (FIH) study[2].

Methods: AMG193 was orally administered in continuous 28-day cycles to patients (pts) with advanced MTAP-null solid tumors. Dose escalation proceeded via a BLRM method. The primary objectives include safety, tolerability, and identification of the maximum tolerated dose (MTD). Secondary objectives include preliminary antitumor activity by investigator-assessed RECIST, pharmacokinetics (PK) and pharmacodynamic (PD) effects.[2]
Results: As of August 8, 2023, 47 pts with MTAP-null cancer (PDAC n = 10; NSCLC n = 6; CCA = 5; MESO n = 3; others n = 23) were enrolled in seven escalating cohorts. Five pts had DLTs, and exploration continues per protocol to identify the MTD. The most common TRAEs were nausea (45%), fatigue (26%), decreased appetite (17%), and vomiting (17%). Preliminary PK analyses showed dose-proportional systemic exposure with a half-life of 7–11 hrs. Among 31 pts who had at least one postbaseline scan, there were 5 with confirmed PRs [PDAC (–100%), ovarian Sertoli-Leydig (–59%), RCC (–58%), esophageal (–46%), and gallbladder cancer (–63%), 1 each], 14 with stable disease (including 9 with some degree of tumor shrinkage), and 12 with disease progression. All PRs were ongoing at the data cutoff with treatment durations of 140–275 days. PD effects demonstrated dose-dependent reduction in serum total SDMA levels and complete PRMT5 inhibition was confirmed in five pts with on-treatment biopsies spanning multiple dose levels. Exploratory analysis of changes in variant allele frequency by ctDNA demonstrated rapid treatment effects that was predictive and correlated with response.[2]
Conclusion: AMG 193 is an MTA-cooperative PRMT5 inhibitor designed to induce synthetic lethality in MTAP-null solid tumors while sparing hematologic toxicity. The initial results of the FIH study demonstrate proof-of-concept with encouraging signs of preliminary clinical activity without evidence of myelosuppression. Dose escalation continues to proceed to establish the MTD. AMG 193 has demonstrated promise as a potential new therapeutic for pts with tumors that have MTAP loss[2].

[1]. AMG 193 Effective in Multiple Tumor Types. Cancer Discov. 2023 Dec 12;13(12):2492. doi: 10.1158/2159-8290.CD-NB2023-0079.
[2].Abstract PR006: Initial results from first-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in biomarker-selected solid tumors. Mol Cancer Ther (2023) 22 (12_Supplement): PR006. https://doi.org/10.1158/1535-7163.TARG-23-PR006.
[3]. Shon Booker, et al. Prmts inhibitors. WO2022132914A1. 2022-06-23.

The second-generation PRMT5 inhibitor AMG 193 (Amgen) achieved partial remissions in patients with various tumor types while avoiding the toxicities associated with first-generation drugs. The results, presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapy in Boston, Massachusetts, from October 11-15, offer a potential treatment avenue for 10% to 15% of patients with MTAP-deficient solid tumors. Dr. Jordi Rodón of the University of Texas MD Anderson Cancer Center explained, “PRMT5 is responsible for the methylation and gene silencing of essential cellular proteins, which are dysregulated in cancer.” Dr. Rodón presented these findings at the conference. However, researchers found that broad targeting of PRMT5 leads to severe myelosuppression and other intolerable side effects, necessitating a different treatment approach. Biologically, researchers know that MTAP-deficient tumors accumulate the metabolite MTA. Rotton continued, "Interestingly, MTA is a natural inhibitor of PRMT5, so tumors lacking MTAP accumulate MTA, thus partially inhibiting PRMT5. Through chemical techniques, we can develop drugs that bind to PRMT5 only in the presence of MTA," thereby protecting healthy cells while killing tumor cells. This is the concept behind novel MTA-synergistic PRMT5 inhibitors; AMG 193 is one example. Mirati's MRTX1719 is another. Boston-based Tango Therapeutics, Krakow-based Ryvu Therapeutics, and Shanghai-based Abbisko Therapeutics also presented their preclinical research findings at the Molecular Targets Conference. Tango Therapeutics currently has two PRMT5 inhibitors in early clinical trials, developed in collaboration with the MTA. Rodón and his team, after demonstrating in preclinical studies that AMG 193 could exploit this tumor-specific vulnerability, initiated the drug's first human Phase I clinical trial, recruiting 48 patients with advanced solid tumors. Among them, 10 patients had pancreatic adenocarcinoma, 7 had non-small cell lung cancer, 5 had cholangiocarcinoma, and 3 had mesothelioma; the remaining 23 patients had other types of cancer. All patients had previously tried at least one other therapy, with one-third having tried four or more. Patients received seven different doses of AMG 193, ranging from 40 mg to 1600 mg daily; patients taking higher doses experienced greater tumor shrinkage. Overall, among the 31 patients who underwent at least one scan after starting treatment, 5 patients (with esophageal cancer, pancreatic cancer, renal cell carcinoma, gallbladder cancer, and ovarian Sertoli-stromal cell carcinoma, respectively) achieved partial remission. Another 14 patients had stable disease, with 9 of them experiencing tumor shrinkage. Rodón reported that 39 patients (81.3%) experienced treatment-related adverse events (TRAEs), the most common being nausea, fatigue, loss of appetite, and vomiting, with the highest incidence in the high-dose group. Three patients discontinued treatment due to TRAEs. Rodón noted that AMG 193 did not cause significant granulocytopenia or thrombocytopenia, problems previously shown to occur with first-generation PRMT5 inhibitors. “Novel MTA-synergistic PRMT5 inhibitors look promising,” said Pasi Jänne, MD, of the Dana-Farber Cancer Institute in Boston, who participated in the MRTX1719 study (Cancer Discov 2023;11:2412–31). "MTAP deficiency is widespread in various cancers, which is an advantage for this type of drug because there are currently no approved targeted therapies for many cancers with MTAP deficiency, such as mesothelioma or pancreatic cancer," Jänne said. However, because MTAP deficiency is found in a variety of malignancies, he cautioned that more patients need to be recruited for this trial and others "to truly understand its efficacy." David Kwiatkowski, MD, PhD, of Brigham and Women's Hospital and Dana-Farber Cancer Institute in Boston, who also participated in the Mirati study, expressed "great enthusiasm and optimism" for the future of MTA synergistic with PRMT5 inhibitors. He has a mesothelioma patient who participated in the MRTX1719 study, and that patient "received excellent results. He has been taking the drug for a year, tolerated it well, and feels great." In the MRTX1719 Phase I/II study, 6 out of 18 evaluable patients confirmed a response to the drug. Kwiatkowski continued, saying that thanks to preclinical and early clinical studies, the mechanism of action of MTA synergistic with PRMT5 inhibitors "has been validated." “This is not just one drug, nor just one company. It's multiple drugs, multiple companies. That's exciting.” — Susanna Ross.
Reference: https://aacrjournals.org/cancerdiscovery/article/13/12/2492/731594/AMG-193-Effective-in-Multiple-Tumor-TypesAMG-193

C22H19F3N4O3

444.406475305557

444.14

2790567-82-5

164536956

White to light yellow solid powder

1.8

1

9

2

32

688

1

C1COC[C@@H](N1C(=O)C2=NC=C3C(=C2)C4=C(COC4)C(=N3)N)C5=CC=C(C=C5)C(F)(F)F

BFEBTMFPRJPBTK-LJQANCHMSA-N

InChI=1S/C22H19F3N4O3/c23-22(24,25)13-3-1-12(2-4-13)19-11-31-6-5-29(19)21(30)17-7-14-15-9-32-10-16(15)20(26)28-18(14)8-27-17/h1-4,7-8,19H,5-6,9-11H2,(H2,26,28)/t19-/m1/s1

(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone

AMG193; AMG-193

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)