Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of ASTX029 that can be given in combination with ASTX727 to participants who have RAS-mutant MDS or MDS/MPN. The goal of Part 2 of this clinical research study is to learn if the dose of ASTX029 found in Part 1 can help to control the disease when used in combination with ASTX727.

开始日期2025-01-31

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT06113289

/ Withdrawn临床1/2期IIT

A Phase 1B/2A Trial of Combination of ASTX727 With ASTX029 in Acute Myeloid Leukemia

To find the recommended dose of the study drugs ASTX727 and ASTX029 that can be given to patients with relapsed/refractory AML. The goal of Part 2 of the study is to learn if the dose of study drugs found in Part 1B can help to control AML.

开始日期2024-02-08

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT04466514

/ Completed临床1期

A Phase 1, 3-Way Crossover Study to Evaluate the Effect of Food on Pharmacokinetics of ASTX029

Open-label, single dose, randomized, three-period, crossover design study to evaluate the effect of food on the bioavailability of a single oral dose of ASTX029 in healthy adult male and female participants.
Following a screening period of up to 28 days, eligible participants will be enrolled and randomized to receive a single treatment (A, B, C) in a random order, with each treatment separated by an approximate 5-day washout period. The duration of the study is expected to be approximately 42 days.

开始日期2020-07-23

申办/合作机构

Astex Pharmaceuticals, Inc.

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项与 Beroterkib 相关的文献（医药）

2021-10-01·Molecular cancer therapeutics2区 · 医学

ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK

2区 · 医学

Article

作者: Rees, David C. ; Wallis, Nicola G. ; Hindley, Christopher J. ; Reader, Michael ; Munck, Joanne M. ; Ferraldeschi, Roberta ; Norton, David ; Courtin, Aurélie ; Bevan, Luke ; Woolford, Alison J.-A. ; Shah, Alpesh D. ; Stanczuk, Lukas ; Brothwood, Jessica L. ; Muench, Sandra ; Rich, Sharna J. ; Lyons, John F. ; Kucia-Tran, Justyna ; Berdini, Valerio ; Heightman, Tom D. ; East, Charlotte ; Richardson, Caroline J. ; Murray, Christopher W. ; Martins, Vanessa ; Castro, Juan ; Wilsher, Nicola E. ; Thompson, Neil T. ; O'Reilly, Marc

Abstract:

The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Because of its distinctive ERK-binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, ribosomal S6 kinase (RSK), were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human phase I–II clinical trial in patients with advanced solid tumors (NCT03520075).

2021-08-26·Journal of medicinal chemistry1区 · 医学

Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2

1区 · 医学

Article

作者: Griffiths-Jones, Charlotte M. ; Watts, John ; Day, James E. H. ; Pathuri, Puja ; Walton, Hugh ; Wallis, Nicola G. ; Shah, Alpesh ; Munck, Joanne M. ; Palmer, Nicholas ; Onions, Stuart ; Cooke, Michael ; Courtin, Aurélie ; Bevan, Luke ; Shannon, Jonathan ; Norton, David ; Coyle, Joseph E. ; O’Reilly, Marc ; Muench, Sandra ; Woolford, Alison J.-A. ; Peakman, Torren M. ; Cousin, David ; Reader, Michael ; Buck, Ildiko M. ; Rich, Sharna J. ; Berdini, Valerio ; Kucia-Tran, Justyna ; East, Charlotte ; Howard, Steven ; Murray, Christopher W. ; Fazal, Lynsey ; Rees, David C. ; Martins, Vanessa ; Heightman, Tom D. ; Carr, Maria G. ; Wilsher, Nicola E.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.

Journal of experimental & clinical cancer research : CR

Auranofin repurposing for lung and pancreatic cancer: low CA12 expression as a marker of sensitivity in patient-derived organoids, with potentiated efficacy by AKT inhibition

Article

作者: Le Compte, Maxim ; Hendriks, Jeroen M H ; Vanlanduit, Steve ; Boullosa, Laurie Freire ; Seghers, Sofie ; Van Schil, Paul ; Lin, Abraham ; Prenen, Hans ; Smits, Evelien ; Fortes, Felicia Rodrigues ; De La Hoz, Edgar Cardenas ; Lardon, Filip ; Peeters, Marc ; Roeyen, Geert ; Dijkstra, Krijn K ; Deben, Christophe

Abstract:

Background:

This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in oncology offers a cost-effective and time-efficient approach to developing new cancer therapies. Our research focuses on evaluating AF's selective cytotoxicity against cancer cells, identifying RNAseq-based biomarkers to predict AF response, and finding the most effective co-therapeutic agents for combination with AF.

Methods:

Our investigation employed a comprehensive drug screening of AF in combination with eleven anticancer agents in cancerous PDAC and NSCLC patient-derived organoids (n = 7), and non-cancerous pulmonary organoids (n = 2). Additionally, we conducted RNA sequencing to identify potential biomarkers for AF sensitivity and experimented with various drug combinations to optimize AF's therapeutic efficacy.

Results:

The results revealed that AF demonstrates a preferential cytotoxic effect on NSCLC and PDAC cancer cells at clinically relevant concentrations below 1 µM, sparing normal epithelial cells. We identified Carbonic Anhydrase 12 (CA12) as a significant RNAseq-based biomarker, closely associated with the NF-κB survival signaling pathway, which is crucial in cancer cell response to oxidative stress. Our findings suggest that cancer cells with low CA12 expression are more susceptible to AF treatment. Furthermore, the combination of AF with the AKT inhibitor MK2206 was found to be particularly effective, exhibiting potent and selective cytotoxic synergy, especially in tumor organoid models classified as intermediate responders to AF, without adverse effects on healthy organoids.

Conclusion:

Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes.

项与 Beroterkib 相关的新闻（医药）

2026-07-06

·Firstwordpharma

Roche inks $490M+ breast cancer therapeutics deal with Otsuka's Astex

Roche's Genentech unit signed a research collaboration and licensing pact potentially worth over $490 million with Astex Pharmaceuticals — a wholly-owned subsidiary of Otsuka Pharmaceutical — centred on the development of small-molecule drugs with selective inhibitory activity for breast cancer.The deal announced Monday gives Genentech exclusive global rights to assets from Astex's existing programme that utilises fragment-based drug discovery to develop molecules targeting a key cell-cycle-dependent regulator in breast cancer. The programme originated from an earlier collaborative project under Astex's alliance with Newcastle University and Cancer Research Horizons.The companies will also collaborate to optimise preclinical-ready lead compounds, which Genentech will then solely advance through preclinical testing and clinical development, alongside commercialising any resulting medicines.“Working alongside partners like Astex… in pursuit of precision therapies against cell-cycle regulators… we follow the science to focus our innovation on the areas of the highest unmet need,” said Boris Zaïtra, head of Roche's corporate business development team.As per the agreed terms, Genentech will make an upfront payment of $25 million, with Astex eligible for additional milestones plus tiered sales royalties.Aside from the Genentech deal, Astex — alongside Otsuka subsidiary Taiho Pharmaceutical — inked a key partnership with Merck & Co. in 2020 to develop small-molecule inhibitors in oncology. Merck and Astex further deepened their alliance in 2023, adding more cancer candidates. Meanwhile, last year, Astex outlicensed to Mosaic Therapeutics two clinical-stage assets: ASTX029, an ERK1/2 inhibitor, and ASTX295, an MDM2 antagonist.

引进/卖出

2026-04-01

·BioSpace

Mosaic Therapeutics appoints Dr Vince O’Neill, MD, as Head of R&D

- Medical oncologist and accomplished clinical leader brings deep development and industry experience to Mosaic’s Executive Leadership team - Vince will lead research and development for Mosaic’s drug combination programs, including the build-out of the Company’s early pipeline CAMBRIDGE, England--(BUSINESS WIRE)--Mosaic Therapeutics, Ltd, (‘Mosaic’, or ‘the Company’) a clinical-stage oncology therapeutics company developing next-generation, Synergistic Precision combination therapies, today announced the appointment of Dr Vince O’Neill as Head of Research and Development (R&D) to support its next phase of growth. “We are delighted to welcome Vince to the Mosaic leadership team at this pivotal stage of the company’s evolution,” said Thomas Fuchs, CEO, Mosaic Therapeutics. “His deep expertise in targeted oncology drug development and diagnostics will be instrumental as we advance our pipeline to bring transformative therapies to patients in need.” Vince is a board-certified medical oncologist and highly experienced biotechnology executive, bringing over two decades of therapeutic and diagnostic R&D experience within industry to Mosaic Therapeutics, with a track record spanning from IND through to NDA/BLA/MAA approval. Most recently he served at BioXcel Therapeutics as EVP, Head of Product Development and Chief Medical Officer, having previously held roles including Chief R&D Officer at OnkosXcel Therapeutics, and CMO roles at MIRNA Therapeutics and Exosome Diagnostics. Additionally, he has held various senior clinical development and medical leadership positions at Sanofi-Aventis, GSK, Genentech and Roche, playing an instrumental role in the development and commercialisation of multiple high-impact oncology therapeutics, including Avastin, Venclexta, Tarceva, Merkinist, and Tafinlar. In early-stage biotech, he has also secured successful public ($420M) and private ($65M series B) financing raises as part of executive leadership teams. He obtained his BSc, MD and MBChB in Medicine from the University of Glasgow. Vince O’Neill, Head of R&D, Mosaic Therapeutics, commented: “ I look forward to working closely with the Board and the team to advance our programs into the clinic and for the opportunity to develop novel combination therapies for cancer patients, utilising innovative biomarker strategies to maximise patient benefit.” About Mosaic Therapeutics Mosaic Therapeutics is an oncology therapeutics company building the category leader in Synergistic Precision Oncology. The company’s mission is to tackle cancers with substantial unmet need and few targeted treatment options, by applying its advanced experimental and computational platform to identify oncology combinations that have synergistic activity in biomarker-defined patient populations. Born out of pioneering research at the Wellcome Sanger Institute, in collaboration with the Netherlands Cancer Institute, Mosaic has active programs across a variety of oncology indications and disease biology pathways. The Company’s pipeline is anchored by ASTX295, an MDM2 antagonist, and ASTX029, an ERK1/2 inhibitor, both in-licensed from Astex Pharmaceuticals in April 2025. Mosaic’s first clinical combination study is expected to commence in early 2027. LinkedIn: Website: Contacts Thomas Fuchs CEO, Mosaic Therapeutics E: info@mosaic-tx.com

高管变更

2026-03-24

·BioSpace

Mosaic Therapeutics to Present Poster Highlighting Preclinical Data for Lead Program MOS101 at the American Association for Cancer Research (AACR) Annual Meeting 2026

First preclinical data on the Company’s lead program MOS101: a combination of ASTX295, a next-generation, clinical-stage MDM2 antagonist, and olaparib, an FDA-approved PARP inhibitor, in biomarker-selected solid tumors Additional data showcasing Mosaic’s Discovery Platform, PRIME, will be presented CAMBRIDGE, England--(BUSINESS WIRE)--Mosaic Therapeutics, Ltd, (‘Mosaic’, or ‘the Company’) a clinical-stage oncology therapeutics company building the category leader in Synergistic Precision Oncology, today announced it will hold a poster presentation at the American Association for Cancer Research (AACR) Annual Meeting 2026, taking place April 17-22 in San Diego, CA. Poster Presentation Details: Title: "Combination of the MDM2 antagonist ASTX295 and olaparib as a novel treatment option for BRCA2 mutant, TP53 wild-type solid tumors” Abstract Number: 3053 Date and Time: Monday, April 20, 2026, 2:00PM – 5:00PM PST Session Category: Novel Targets and Pathways Session: PO.ET09.09 Location: Poster Section 15 For more information and to view the Company’s abstract, visit the AACR Annual Meeting website . About ASTX295 ASTX295 is a potent, highly selective, potentially best-in-class MDM2 antagonist that has completed a phase I study (NCT03975387) in over 100 patients with advanced solid tumors. Rationally designed to exhibit a short half-life, ASTX295 has demonstrated a compelling safety pro minimal hematological toxicities, enabling use as a combination therapy. MDM2 is a clinically validated target for cancer therapy, frequently overexpressed across multiple tumor types. As the primary negative regulator of the p53 tumor suppressor protein, MDM2 inhibition leads to p53 stabilization and re-activation, inducing cell cycle arrest and apoptosis. Mosaic Therapeutics announced the in-licensing of ASTX295, alongside ASTX029 (an ERK1/2 inhibitor), from Astex Pharmaceuticals in April 2025, and holds full development and commercialization rights. About MOS101 Plans for a Phase 1b/2a study evaluating the combination of ASTX295 with olaparib (an approved PARP inhibitor) for patients with biomarker-selected solid tumors are being finalized. About Mosaic Therapeutics Mosaic Therapeutics is an oncology therapeutics company building the category leader in Synergistic Precision Oncology. The company’s mission is to tackle cancers with substantial unmet need and few targeted treatment options, by reinventing the traditional approach to discovering and developing novel combination medicines. Born out of pioneering research at the Wellcome Sanger Institute, in collaboration with the Netherlands Cancer Institute, and anchored around a proprietary platform that has seen 20 years of fine-tuning and development, Mosaic has active programs across a variety of oncology indications and disease biology pathways. Mosaic is applying its advanced experimental and computational platform to identify oncology combinations that have synergistic activity in biomarker-defined patient populations. The Company’s pipeline is anchored by ASTX295, an MDM2 antagonist, and ASTX029, an ERK1/2 inhibitor, both in-licensed from Astex Pharmaceuticals in April 2025. Mosaic’s first clinical combination study is expected to commence in early 2027. LinkedIn: Website: Contacts Thomas Fuchs CEO, Mosaic Therapeutics E: info@mosaic-tx.com

临床1期AACR会议

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外链

KEGG	Wiki	ATC	Drug Bank
D12865	-	-	-

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	临床2期	美国	Astex Pharmaceuticals, Inc.	2018-05-10
晚期恶性实体瘤	临床2期	美国	Taiho Oncology, Inc.	2018-05-07
晚期恶性实体瘤	临床2期	法国	Taiho Oncology, Inc.	2018-05-07
晚期恶性实体瘤	临床2期	西班牙	Taiho Oncology, Inc.	2018-05-07
晚期恶性实体瘤	临床2期	英国	Taiho Oncology, Inc.	2018-05-07
结直肠癌	临床阶段不明	英国	Astex Pharmaceuticals, Inc.	-
KRAS突变非小细胞肺癌	临床阶段不明	英国	Astex Pharmaceuticals, Inc.	-
黑色素瘤	临床阶段不明	英国	Astex Pharmaceuticals, Inc.	-
胰腺癌	临床阶段不明	英国	Astex Pharmaceuticals, Inc.	-
急性髓性白血病	临床前	美国	Astex Pharmaceuticals, Inc.	2020-11-14

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03520075 (ESMO2024) 人工标引	临床1/2期	MAPK阳性肿瘤 genomic alterations in the MAPK pathway	32	ASTX029 200 mg	醖顧選憲艱蓋糧淵選範(艱鏇艱構遞製鬱糧築艱) = 願積艱衊製艱鏇廠鬱齋窪簾廠窪夢醖範觸艱餘 (鬱餘廠築構築餘齋簾壓, 1.0 ~ 24.0) 更多	积极	2024-09-14
NCT03520075 (ASCO2022) 人工标引	临床1期	实体瘤 KRAS Mutation	76	ASTX 029 (Phase 1A)	膚廠鹽鏇壓鏇願糧鹹憲(糧鹽積網願衊製鏇廠壓) = 夢繭構積憲齋網築獵鹽淵積餘製遞簾鬱積壓鹹 (觸衊選齋齋遞廠觸艱壓 ) 更多	积极	2022-06-02
NCT03520075 (ASCO2022) 人工标引	临床1期	实体瘤 KRAS Mutation	76	ASTX 029 (Phase 1B)	鏇顧夢築鬱襯積鏇廠願(廠製餘網齋觸壓齋獵範) = 醖餘觸窪淵獵夢選鏇獵壓蓋憲襯憲鏇構顧範鹹 (願窪衊鹹壓醖廠壓淵鹹 )	积极	2022-06-02
NCT03520075 (AACR 12021 \| AACR 22021) 人工标引	临床1期	实体瘤	56	ASTX029	簾憲淵遞繭衊憲獵醖襯(觸構觸醖簾獵餘醖範壓) = 1/6 at the 200 mg dose level（Cohort 5, PiB/fed）（grade 3 maculopapular rash）；1 pt at the 280 mg dose level（Cohort 12, tablet/fasting）（grade 2 central serous retinopathy）鑰窪選獵構鹽願齋襯鑰 (獵鹽獵襯夢遞餘壓構齋 ) 更多	积极	2021-07-01