Delving into the Latest Updates on Beroterkib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

ERK1 x ERK2

Action

inhibitors

Mechanism

ERK1 inhibitors(Extracellular-signal-regulated kinase1 inhibitors), ERK2 inhibitors(Extracellular-signal-regulated kinase 2 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [2]

Active Indication

Advanced Malignant Solid NeoplasmColorectal CancerKRAS mutant Non-small Cell Lung Cancer+ [2]

Inactive Indication

Acute Myeloid Leukemia

Originator Organization

Astex Pharmaceuticals, Inc.

Active Organization

Taiho Oncology, Inc.

Astex Pharmaceuticals, Inc.

Inactive Organization-

Drug Highest PhasePhase 1/2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC29H33ClFN5O6

InChIKeyZZOBEXXCVGOKMK-JSYWXJBKSA-N

CAS Registry2696306-32-6

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.

Start Date31 Jan 2025

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

NCT06113289

/ WithdrawnPhase 1/2IIT

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.

Start Date08 Feb 2024

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

NCT04466514

/ CompletedPhase 1

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.

Start Date23 Jul 2020

Sponsor / Collaborator

Astex Pharmaceuticals, Inc.

100 Clinical Results associated with Beroterkib

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100 Translational Medicine associated with Beroterkib

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100 Patents (Medical) associated with Beroterkib

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4

Literatures (Medical) associated with Beroterkib

01 Oct 2021·Molecular Cancer TherapeuticsQ2 · MEDICINE

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

Q2 · MEDICINE

Article

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

AbstractThe 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).

26 Aug 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

An Analysis of Successful Hit-to-Clinical Candidate Pairs

Author: Brown, Dean G.

An anal. of 156 published/clin. candidates from the Journal of Medicinal Chem. between 2018 and 2021 was conducted to identify lead generation strategies most frequently employed leading to drug candidates.As in a previous publication, the most frequent lead generation strategies resulting in clin. candidates were from known compounds (59%) followed by random screening approaches (21%).The remainder of the approaches included directed screening, fragment screening, DNA-encoded library screening (DEL), and virtual screening.An anal. of similarity was also conducted based on Tanimoto-MCS and revealed most clin. candidates were distant from their original hits; however, most shared a key pharmacophore that translated from hit-to-clin. candidate.An examination of frequency of oxygen, nitrogen, fluorine, chlorine, and sulfur incorporation in clin. candidates was also conducted.The three most similar and least similar hit-to-clin. pairs from random screening were examined to provide perspective on changes that occur that lead to successful clin. candidates.

100 Deals associated with Beroterkib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	France	Taiho Oncology, Inc.	10 May 2018
Advanced Malignant Solid Neoplasm	Phase 2	United Kingdom	Taiho Oncology, Inc.	10 May 2018
Advanced Malignant Solid Neoplasm	Phase 2	Spain	Taiho Oncology, Inc.	10 May 2018
Advanced Malignant Solid Neoplasm	Phase 2	United States	Taiho Oncology, Inc.	10 May 2018
Acute Myeloid Leukemia	Preclinical	United States	Astex Pharmaceuticals, Inc.	14 Nov 2020
Solid tumor	Preclinical	United States	Astex Pharmaceuticals, Inc.	10 May 2018

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03520075 (ESMO2024) Manual	Phase 1/2	MAPK positive Neoplasms genomic alterations in the MAPK pathway	32	ASTX029 200 mg	(rpwedzvptj) = bgiojyyptn jwqddojryy (pxfnzxsldu, 1.0 - 24.0) View more	Positive	14 Sep 2024
ASH2023	Not Applicable	Acute Myeloid Leukemia	-	ASTX029	(avykjfirym) = lbegvkwbkz itwtigtnpz (buyvprowke )	-	10 Dec 2023
ASH2023	Not Applicable	Acute Myeloid Leukemia	-	Venetoclax	(avykjfirym) = rqsfjwugji itwtigtnpz (buyvprowke )	-	10 Dec 2023
NCT03520075 (ASCO2022) Manual	Phase 1	Solid tumor KRAS Mutation	76	ASTX 029 (Phase 1A)	(nvdbdevvii) = zfpguabouy lxaikqgkpp (oxqbaeezgb ) View more	Positive	02 Jun 2022
NCT03520075 (ASCO2022) Manual	Phase 1	Solid tumor KRAS Mutation	76	ASTX 029 (Phase 1B)	(lxvxxcjsak) = fiofgccaou palsmbrfzs (meprgsusyn )	Positive	02 Jun 2022
NCT03520075 (AACR 12021 \| AACR 22021) Manual	Phase 1	Solid tumor	56	ASTX029	(ggyvmjvneq) = 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） puqtuvgwyo (ahbcwkrztk ) View more	Positive	01 Jul 2021