P1/2, N=225, Recruiting, Tango Therapeutics, Inc. | N=159 --> 225

P1, N=114, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

No abstract available

P1, N=500, Recruiting, Amgen | Trial completion date: Jun 2032 --> Oct 2031 | Trial primary completion date: Jun 2029 --> Oct 2028

MRTX1719 reduces PRMT5 activity, leading to cell cycle arrest by increasing the proportion of cells in the G0/G1 phase. Moreover, MRTX1719 exhibits synergistic anticancer effects with oxaliplatin and gemcitabine in MTAP-deficient cancer cells.

P2, N=200, Not yet recruiting, Amgen | Trial completion date: Sep 2029 --> Feb 2029 | Trial primary completion date: Sep 2027 --> Feb 2027

The findings suggest that EGCG effectively inhibits PRMT5 and EZH2, underscoring its potential for combined therapeutic strategies in cancer treatment.

P1/2, N=192, Active, not recruiting, Tango Therapeutics, Inc. | Recruiting --> Active, not recruiting

P1, N=92, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P1, N=8, Not yet recruiting, Bristol-Myers Squibb

P1/2, N=184, Recruiting, Amgen | Trial completion date: Dec 2026 --> Sep 2027

In view of their importance, this paper reviews the first generation of PRMT5 inhibitors obtained by high-throughput screening, virtual screening, lead compound optimization and substitution modification, as well as novel PRMT5 inhibitors obtained by PROTAC technology and by synthetic lethal principle. Finally, by comparing the differences between the first generation and the second generation, the challenges and future development directions of PRMT5 inhibitors are discussed.

P1/2, N=184, Recruiting, Amgen | Trial completion date: Aug 2026 --> Dec 2026 | Trial primary completion date: Nov 2025 --> Mar 2026

P1, N=188, Recruiting, Amgen | Trial completion date: Nov 2027 --> Apr 2028 | Trial primary completion date: Nov 2025 --> May 2026

Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.

Here we evaluate the highly selective first-in-class PRMT5 inhibitor GSK3203591 and its in vivo analogue GSK3326593 as targeted therapeutics for MNA neuroblastoma...In vivo efficacy of GSK3326593 is confirmed by increased survival of Th-MYCN mice, with drug treatment triggering splicing events and protein decreases consistent with in vitro data. Together our study demonstrates the PRMT5-dependent spliceosomal vulnerability of MNA neuroblastoma and identifies the epitranscriptome and glutamine metabolism as critical determinants of this sensitivity.

Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of MTAP-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.

AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on ORR and ctDNA clearance.

The safety profile was broadly consistent with other published PRMT5 inhibitor studies. ClinicalTrials.gov: NCT03614728.

AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.

P1, N=92, Not yet recruiting, BeiGene

P2, N=200, Not yet recruiting, Amgen

Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells...We also show that the methylation of vCyclin by PRMT5 positively regulates the phosphorylate retinoblastoma protein (pRB) pathway. Taken together, our findings reveal an important regulatory effect of PRMT5 on vCyclin that facilitates cell cycle progression and proliferation, which provides a potential therapeutic target for KSHV-associated malignancies.

Inspired by the surprising finding that PRMT5 negatively correlates with tumor immune infiltration and transcriptionally suppresses an immune-gene program, we further show that although PRMT5 inhibitor (PRMT5i) EPZ015666 or anti-PD-1 immunotherapy alone exhibits limited antitumor effects, combination of PRMT5i with anti-PD-1 displays superior efficacy in inhibiting castration-resistant PCa (CRPC) in vivo. Finally, to expand the potential use of PRMT5i through a synthetic lethality concept, we also perform a global CRISPR/Cas9 knockout screen to unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target CRPC when used in combination with PRMT5i at low doses. Collectively, our findings establish a rationale to exploit PRMT5i in combination with immunotherapy or other targeted therapies to treat aggressive PCa.

P1/2, N=649, Recruiting, Amgen | Trial completion date: Mar 2029 --> Dec 2027 | Trial primary completion date: Nov 2027 --> Mar 2026

P1/2, N=580, Recruiting, Mirati Therapeutics Inc. | N=370 --> 580

Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models.

Treatment of mice with LLY-283 decreased tumor PRMT5 activity and significantly enhanced the radiation-induced growth delay. These results suggest that PRMT5 is a tumor selective target for radiosensitization.

Treatment options are limited to Tebentafusp in patients with HLA-A*02:01 mutation with immunotherapy and chemotherapy yielding poor results...In a recent phase I trial of a PRMT5 inhibitor, PRT811, clinical activity was described in cases of CAUM. 676 CAUM and 9666 CASM patients underwent hybrid capture based CGP to evaluate genomic alterations (GA)... Although MTAP loss is less frequent in CAUM than in CASM, the recent evidence that this genomic alteration predicts responsiveness to PRMT5 inhibition is noteworthy. This highlights the importance of further investigating this biomarker for patients with this rare and clinically aggressive type of cancer.

P1, N=500, Recruiting, Amgen | Trial completion date: Nov 2029 --> May 2032 | Trial primary completion date: Nov 2026 --> May 2029

P1, N=188, Recruiting, Amgen | N=282 --> 188

P1, N=282, Recruiting, Amgen | Trial completion date: May 2028 --> Nov 2027 | Trial primary completion date: May 2026 --> Nov 2025

P1/2, N=184, Recruiting, Amgen | Trial completion date: Jul 2026 --> Dec 2026

P1, N=500, Recruiting, Amgen | Not yet recruiting --> Recruiting

P1, N=282, Recruiting, Amgen | Not yet recruiting --> Recruiting

PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection.

Moreover, PRMT5 inhibitors including SH3765 and EPZ015666 worked through blocking SREBP1/2 and FASN expression in MCL. Furthermore, PRMT5 was significantly associated with MYC expression in 105 MCL samples and the GEO database (GSE93291). CRISPR MYC knockout indicated PRMT5 can promote MCL outgrowth by inducing SREBP1/2 and FASN expression through the MYC pathway.

P1, N=282, Not yet recruiting, Amgen

Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.

Knockdown of DKK1 or treatment with the PRMT5 inhibitor CMP5 in combination with doxorubicin yielded a synergistic anti-tumor effect in KRAS mutant, but not KRAS wild-type, CRC cells. These findings suggest that PRMT5 regulates DKK1 expression in CRC and that inhibition of PRMT5 modulates DKK1 expression in such a way that reduces CRC cell growth.

P1/2, N=17, Terminated, SK Life Science, Inc. | N=96 --> 17 | Trial completion date: Sep 2024 --> Mar 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2024 --> Mar 2024; The study has been terminated based on portfolio prioritization. No safety trends or issues were identified at any dose level.

P1, N=500, Not yet recruiting, Amgen