Delving into the Latest Updates on ARQ-751 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Vevorisertib, ARQ 751, ARQ-751

+ [1]

Target

Akt x Akt-1

Action

inhibitors

Mechanism

Akt inhibitors(Proto-oncogene proteins c-akt inhibitors), Akt-1 inhibitors(Serine/threonine-protein kinase AKT inhibitors)

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Endometrial Carcinoma

Inactive Indication

Advanced Malignant Solid Neoplasm

Originator Organization

ArQule, Inc.

Active Organization

ArQule, Inc.South Texas Accelerated Research Therapeutics LP

Inactive Organization

Merck GmbH

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC35H38N8O

InChIKeyNZDSLYATTDIDPH-UHFFFAOYSA-N

CAS Registry1416775-46-6

The primary objectives of this study are: Part 1 - Vevorisertib as single agent: To assess the safety and tolerability of vevorisertib in participants with advanced solid tumors with v-Akt murine thymoma viral oncogene homolog (AKT) 1, 2, 3 genetic alterations, activating phosphatidylinositol-3-kinase (PI3K) mutations, phosphatase and tensin homolog deleted on chromosome ten (PTEN)-null, or other known actionable PTEN mutations; Part 2 - Vevorisertib in combination with other anti-cancer agents: To assess the safety and tolerability of vevorisertib in combination with paclitaxel or fulvestrant in participants with advanced, inoperable, metastatic and/or recurrent solid tumors with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) / PTEN actionable mutations and/or AKT genetic alterations.

Start Date26 Jun 2016

Sponsor / Collaborator-

100 Clinical Results associated with ARQ-751

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100 Translational Medicine associated with ARQ-751

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100 Patents (Medical) associated with ARQ-751

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6

Literatures (Medical) associated with ARQ-751

15 Jun 2023·Cancer

Phase 1b study of pan-AKT inhibitor vevorisertib alone or with paclitaxel or fulvestrant in PIK3CA/AKT/PTEN-mutated advanced solid tumors.

Article

Author: Ulahannan, Susanna V ; Pant, Shubham ; Braiteh, Fadi S ; Strauss, James F ; Hamilton, Erika ; Liaw, Danny Chih Hsun ; Huang, Mo

BACKGROUND:

In this first-in-human phase 1b study (ClinicalTrials.gov identifier NCT02761694) of advanced solid tumors with PIK3CA/AKT/PTEN mutations, the authors investigated the safety and efficacy of the pan-AKT inhibitor vevorisertib (MK-4440; ARQ 751) as monotherapy or with paclitaxel or fulvestrant.

METHODS:

Patients with histologically confirmed, advanced or recurrent, PIK3CA/AKT/PTEN-mutated solid tumors, measurable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status ≤1 received vevorisertib (dose range, 5-100 mg) alone or with paclitaxel 80 mg/m² or fulvestrant 500 mg. The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1.

RESULTS:

Of 78 patients enrolled, 58 received vevorisertib monotherapy, 10 received vevorisertib plus paclitaxel, and nine received vevorisertib plus fulvestrant. Dose-limiting toxicity occurred in three patients (vevorisertib monotherapy, n = 2 [grade 3 pruritic and maculopapular rashes]; vevorisertib plus paclitaxel, n = 1 [grade 1 asthenia]). Across doses, treatment-related AEs occurred in 46 patients (79%) with vevorisertib monotherapy, in 10 patients (100%) with vevorisertib plus paclitaxel, and in nine patients (100%) with vevorisertib plus fulvestrant; and grade 3 treatment-related AEs occurred in 13 (22%), 7 (70%), and 3 (33%) patients, respectively. No grade 4/5 treatment-related AEs occurred. Maximum vevorisertib concentrations were reached 1-4 hours after dosing; the elimination half-life ranged from 8.8 to 19.3 hours. The objective response rate was 5% with vevorisertib monotherapy (three partial responses), 20% with vevorisertib plus paclitaxel (two partial responses), and 0% with vevorisertib plus fulvestrant.

CONCLUSIONS:

Vevorisertib alone or with paclitaxel or fulvestrant had a manageable safety profile, and vevorisertib alone or with paclitaxel had minimal to modest antitumor activity in this patient population with PIK3CA/AKT/PTEN-mutated advanced solid tumors.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT02761694.

18 Aug 2020·British journal of cancerQ1 · MEDICINE

A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity

Q1 · MEDICINE

Article

Author: Raynaud, Florence ; Schwartz, Brian ; Chung, Yuen-Li ; Heuss, Sara Farrah ; Casado, Pedro ; Cutillas, Pedro R ; Hussain, Aasia ; Kostaras, Eleftherios ; Yandim, Cihangir ; Vivanco, Igor ; Kaserer, Teresa ; Hayes, Angela ; Lazaro, Glorianne ; Palaskas, Nicolaos ; Yu, Yi

Abstract:

Background:

AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants.

Methods:

We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity.

Results:

Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations.

Conclusions:

These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options.

01 Dec 2018·BMC cancerQ2 · MEDICINE

Generation and characterization of MEK and ERK inhibitors- resistant non-small-cells-lung-cancer (NSCLC) cells

Q2 · MEDICINE

ArticleOA

Author: Caiola, Elisa ; Iezzi, Alice ; Scagliotti, Arianna ; Broggini, Massimo

BACKGROUND:

The RAS/RAF/MEK/ERK pathway is one of the most downregulated pathway in cancer. Inhibitors of RAF and MEK have established clinical use while ERK inhibitors recently faced the clinic. We aimed to generate resistant cell lines which could be helpful for defining new combinations able to overcome resistance.

METHODS:

the human NSCLC cell line NCI-H727, sensitive to both MEK and ERK inhibitors, was treated with increasing concentrations of MEK162 (as MEK inhibitor) or SCH772984 as ERK inhibitor.

RESULTS:

we successfully obtained a MEK resistant subline (H727/MEK, after 40 passages) as well as an ERK resistant subline (H727/SCH, after 18 passages). The two resistant sublines H727/MEK and H727/SCH were cross-resistant to ERK and MEK inhibitors, respectively, but not to RAF inhibitors. The sublines maintained the responsiveness to inhibitors of the parallel PI3K/akt/mTOR pathway as well as to agents with different mechanism of action. Mechanistically, treatment of sensitive and resistant cells with MEK or ERK inhibitors was able to induce a similar inhibition of ERK phosphorylation, while only in parental cells the drugs were able to induce a downregulation of S6 and RSK phosphorylation.

CONCLUSIONS:

these resistant cells represent an important tool for further studies on the mechanisms of resistance and ways to overcome it.

100 Deals associated with ARQ-751

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	United States	Merck GmbH	06 Oct 2019
Advanced Malignant Solid Neoplasm	Phase 1	United States	-	26 Jun 2016
Endometrial Carcinoma	Preclinical	United States	ArQule, Inc.	01 Dec 2015
Endometrial Carcinoma	Preclinical	United States	South Texas Accelerated Research Therapeutics LP	01 Dec 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02761694 (MK-4440-001 \| 4440-001, Pubmed)	Phase 1	Advanced Malignant Solid Neoplasm	78	Vevorisertib monotherapy	upuolzjrlg(sjwnkpmlqk) = occurred in three patients (vevorisertib monotherapy, n = 2 [grade 3 pruritic and maculopapular rashes]; vevorisertib plus paclitaxel, n = 1 [grade 1 asthenia]) kjbkxzomii (ekpoomyepp ) View more	Positive	27 Mar 2023
NCT02761694 (MK-4440-001 \| 4440-001, Pubmed)	Phase 1	Advanced Malignant Solid Neoplasm	78	Vevorisertib plus paclitaxel		Positive	27 Mar 2023
NCT02761694 (MK-4440-001 \| 4440-001, AACR 12018 \| AACR 22018) Manual	Phase 1	HR-positive/HER2-low Solid Tumors AKT1 Mutation \| AKT2 Mutation \| AKT3 Mutation ... View more	15	ARQ-751	pxfqpazymr(arvdozzfoo) = none tgjtijwimt (hwrknkjbch ) View more	Positive	01 Jul 2018