Delving into the Latest Updates on GSK-3326595 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Pemrametostat

+ [2]

Target

PRMT5

Mechanism

PRMT5 inhibitors(Protein arginine methyltransferase 5 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases+ [4]

Active Indication

Acute Myeloid LeukemiaMyelodysplastic SyndromesAstrocytoma+ [6]

Inactive Indication

Early Stage Breast Carcinoma

Originator Organization

Epizyme, Inc.

Active Organization

GSK Plc

Epizyme, Inc.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC24H32N6O3

InChIKeyJLCCNYVTIWRPIZ-NRFANRHFSA-N

CAS Registry1616392-22-3

This study will evaluate the safety, tolerability, and clinical activity of GSK3326595 in participants with relapsed and refractory MDS, chronic myelomonocytic leukemia (CMML), and AML. The study will be conducted in 2 parts: Part 1 will determine the clinical benefit rate (CBR) of GSK3326595 in monotherapy and Part 2 will be expanded to study GSK3326595 in combination with 5-Azacitidine which will be composed of a dose escalation phase followed by dose expansion cohort of GSK3326595.

Start Date16 Oct 2018

Sponsor / Collaborator

GSK Plc

NL-OMON53127

/ CompletedNot Applicable

A phase I, open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin*s lymphoma. - GSK3326595 (9018/0006)

Start Date01 Feb 2017

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with GSK-3326595

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100 Translational Medicine associated with GSK-3326595

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100 Patents (Medical) associated with GSK-3326595

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24

Literatures (Medical) associated with GSK-3326595

23 Sep 2024·Journal for immunotherapy of cancer

MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors.

Article

Author: Peng, Weiyi ; Shi, Leilei ; Wang, Shuyue ; Guerrero, Ashley ; Hou, Jiakai ; Yu, Chengtai ; Liu, Xinli ; Shah, Pooja Anil ; Chen, Taiping ; Stone, Everett M ; Zheng, Ningbo ; Gjuka, Donjeta ; Xu, Han ; Bedford, Mark T ; Sharif, Sana ; He, Wei ; Rodon Ahnert, Jordi ; Fu, Rongjie ; Egan, Nicholas A ; Jaffery, Roshni ; Chen, Si ; Lu, Yue ; Bohat, Ritu

BACKGROUNDHyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer.METHODSIsogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo. Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor.RESULTSGSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors.CONCLUSIONCollectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.

01 Jan 2024·Journal of Biological Chemistry

Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition

Article

Author: Peregrina, Karina ; Tosti, Elena ; Gilaj, Nord ; Edelmann, Winfried ; Shaffer, Karl ; Bedard, Gabriel T ; Schramm, Vern L ; Brew, Isabella ; Augenlicht, Leonard H ; Tyler, Peter C

Homozygous 5'-methylthioadenosine phosphorylase (MTAP) deletions occur in approximately 15% of human cancers. Co-deletion of MTAP and methionine adenosyltransferase 2 alpha (MAT2a) induces a synthetic lethal phenotype involving protein arginine methyltransferase 5 (PRMT5) inhibition. MAT2a inhibitors are now in clinical trials for genotypic MTAP^-/- cancers, however the MTAP^-/- genotype represents fewer than 2% of human colorectal cancers (CRCs), limiting the utility of MAT2a inhibitors in these and other MTAP^+/+ cancers. Methylthio-DADMe-immucillin-A (MTDIA) is a picomolar transition state analog inhibitor of MTAP that renders cells enzymatically MTAP-deficient to induce the MTAP^-/- phenotype. Here, we demonstrate that MTDIA and MAT2a inhibitor AG-270 combination therapy mimics synthetic lethality in MTAP^+/+ CRC cell lines with similar effects in mouse xenografts and without adverse histology on normal tissues. Combination treatment is synergistic with a 10⁴-fold increase in drug potency for inhibition of CRC cell growth in culture. Combined MTDIA and AG-270 decreases S-adenosyl-L-methionine and increases 5'-methylthioadenosine in cells. The increased intracellular methylthioadenosine:S-adenosyl-L-methionine ratio inhibits PRMT5 activity, leading to cellular arrest and apoptotic cell death by causing MDM4 alternative splicing and p53 activation. Combination MTDIA and AG-270 treatment differs from direct inhibition of PRMT5 by GSK3326595 by avoiding toxicity caused by cell death in the normal gut epithelium induced by the PRMT5 inhibitor. The combination of MTAP and MAT2a inhibitors expands this synthetic lethal approach to include MTAP^+/+ cancers, especially the remaining 98% of CRCs without the MTAP^-/- genotype.

01 Jan 2024·Therapeutic Advances in Hematology

Phase I/II study of the clinical activity and safety of GSK3326595 in patients with myeloid neoplasms

Article

Author: Egger, Jacqueline L. ; Abedin, Sameem ; Zajac, Magdalena ; Moroz, Veronica ; Barbash, Olena ; Watts, Justin ; Kremer, Brandon E. ; Bachiashvili, Kimo ; Minden, Mark D. ; Tarkar, Aarti ; Crossman, Timothy ; Brunner, Andrew M. ; Borthakur, Gautam

Background: GSK3326595 is a potent, selective, reversible protein arginine methyltransferase 5 (PRMT5) inhibitor under investigation for treatment of myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). In preclinical models of AML, PRMT5 inhibition decreased proliferation and increased cell death, supporting additional clinical research in myeloid neoplasms. Objectives: To determine the clinical activity, safety, tolerability, dosing, additional measures of clinical activity, pharmacokinetics, and pharmacodynamics of GSK3326595. Design: In part 1 of this open-label, multicenter, multipart, phase I/II study, adults with relapsed/refractory myeloid neoplasms (e.g., MDS, CMML, and AML) received monotherapy with 400 or 300 mg oral GSK3326595 once daily. Study termination occurred prior to part 2 enrollment. Methods: Clinical activity was determined by the clinical benefit rate (CBR; proportion of patients achieving complete remission (CR), complete marrow remission (mCR), partial remission, stable disease (SD) >8 weeks, or hematologic improvement). Adverse events (AEs) were assessed by incidence and severity. Exploratory examination of spliceosome mutations was performed to determine the relationship between genomic profiles and clinical response to GSK3326595. Results: Thirty patients with a median age of 73.5 years (range, 47–90) were enrolled; 13 (43%) and 17 (57%) received 400 and 300 mg of GSK3326595, respectively. Five (17%) patients met CBR criteria: 4 (13%) with SD >8 weeks and 1 (3%) achieving mCR. Of five patients with clinical benefit: three had SRSF2 mutation, one U2AF1, and one was splicing factor wild-type. Frequent GSK3326595-related AEs were decreased platelet count (27%), dysgeusia (23%), fatigue (20%), and nausea (20%). GSK3326595 had rapid absorption, with a Tmax of approximately 2 h and a terminal half-life of 4–6 h. Conclusion: GSK3326595 monotherapy had limited clinical activity in heavily pretreated patients despite robust target engagement. The safety profile was broadly consistent with other published PRMT5 inhibitor studies. Trial registration: ClinicalTrials.gov: NCT03614728.

100 Deals associated with GSK-3326595

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 2	-	GSK Plc	-
Acute Myeloid Leukemia	Phase 2	-	Epizyme, Inc.	-
Myelodysplastic Syndromes	Phase 2	-	Epizyme, Inc.	-
Myelodysplastic Syndromes	Phase 2	-	GSK Plc	-
Metastatic urothelial carcinoma	Phase 1	US	GSK Plc	30 Aug 2016
Metastatic urothelial carcinoma	Phase 1	NL	GSK Plc	30 Aug 2016
Metastatic urothelial carcinoma	Phase 1	CA	GSK Plc	30 Aug 2016
Metastatic urothelial carcinoma	Phase 1	FR	GSK Plc	30 Aug 2016
Non-Hodgkin Lymphoma	Preclinical	US	-	12 Apr 2021
Early Stage Breast Carcinoma	Discovery	CA	GSK Plc	08 Jun 2021

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03614728 (Pubmed \| Ther Adv Hematol) Manual	Phase 1/2	Myeloid Tumor \|	30	GSK3326595 400 mg	(imrlywbeuc) = exawstewav zvaczovtdm (oiwtxoyxya ) Met View more	Negative	01 Jan 2024
NCT02783300 (METEOR-1, ESMO2022) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	218	GSK3326595 300mg/400mg (TNBC)	(xpfoqxrghe) = lmqniwdlvl fxxmakpqje (bvqjrraocm )	Positive	12 Sep 2022
NCT02783300 (METEOR-1, ESMO2022) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	218	GSK3326595 300mg/400mg (mTCC)	(xpfoqxrghe) = vfcqtdxxev fxxmakpqje (bvqjrraocm )	Positive	12 Sep 2022
NCT02783300 (METEOR-1, ESMO2019) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	54	GSK-3326595	(uabrldutlw) = anemia (n = 8 [15%]), thrombocytopenia, neutropenia, and fatigue (each n = 4 [7%]) mycqyhcrjx (lhhkxoqjzp ) View more	Positive	29 Sep 2019