Delving into the Latest Updates on Pexmetinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Pexmetinib hydrochloride

Target

Tie-2 x p38 MAPK

Mechanism

Tie-2 antagonists(TEK receptor tyrosine kinase antagonists), p38 MAPK inhibitors(P38 mitogen-activated protein kinase inhibitors)

Therapeutic Areas

NeoplasmsRespiratory DiseasesSkin and Musculoskeletal Diseases+ [1]

Active Indication

Advanced Malignant Solid NeoplasmMelanomaNon-Small Cell Lung Cancer+ [2]

Inactive Indication

Myelodysplastic Syndromes

Originator Organization

Array BioPharma, Inc.

Active Organization

Array BioPharma, Inc.

Inactive Organization-

Drug Highest PhasePhase 1/2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC31H33FN6O3

InChIKeyLNMRSSIMGCDUTP-UHFFFAOYSA-N

CAS Registry945614-12-0

In this study, the Phase Ib portion aims to establish safety and tolerability of ARRY-614 with either nivolumab or ipilimumab and to determine a recommended phase II dose of ARRY-614 in combination with either nivolumab or nivolumab+ipilimumab immunotherapy in patients with selected advanced solid tumors. The Phase II portion will estimate the efficacy of ARRY-614 in combination with either nivolumab or ARRY-614 + nivolumab+ipilimumab immunotherapy in patients with with NSCLC, HNSCC, melanoma and RCC and melanoma.

Start Date11 Jun 2020

Sponsor / Collaborator

University of Pittsburgh

[+1]

NCT01496495 / CompletedPhase 1

A Study of ARRY-614 in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes

This is a Phase 1 study during which patients with low or intermediate-1 risk myelodysplastic syndromes (MDS) will receive investigational study drug ARRY-614.
This study has 2 parts. In the first part, patients will receive increasing doses of study drug in order to achieve the highest dose of the study drug possible that will not cause unacceptable side effects. Approximately 50 patients from the US will be enrolled in Part 1 (Completed).
In the second part of the study, patients will receive the best dose of study drug determined from the first part of the study and will be followed to see what side effects and effectiveness the study drug has, if any, in treating the cancer. Approximately 30 patients from the US will be enrolled in Part 2 (Completed).

Start Date01 Jan 2012

Sponsor / Collaborator

Array BioPharma, Inc.

NCT00916227 / CompletedPhase 1

A Study of ARRY-614 in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndrome

This is a Phase 1 study during which patients with low or intermediate-1 risk myelodysplastic syndrome (MDS) will receive investigational study drug ARRY-614.
This study has 2 parts. In the first part, patients will receive increasing doses of study drug, given either with food or without food, in order to achieve the highest dose of the study drug possible that will not cause unacceptable side effects. Approximately 60 patients from the US will be enrolled in Part 1 (Completed).
In the second part of this study, patients will receive the best dose of study drug, given either with food or without food, determined from the first part of the study and will be followed to see what side effects and effectiveness the study drug has, if any, in treating the cancer. Approximately 40 patients from the US will be enrolled in Part 2 (Completed).

Start Date01 Jun 2009

Sponsor / Collaborator

Array BioPharma, Inc.

100 Clinical Results associated with Pexmetinib

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100 Translational Medicine associated with Pexmetinib

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100 Patents (Medical) associated with Pexmetinib

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11

Literatures (Medical) associated with Pexmetinib

12 Oct 2024·Journal of Biomolecular Structure and Dynamics

In silico screening combined with bioactivity evaluation to identify AMI-1 as a novel anticancer compound by targeting AXL

Article

Author: Zhu, Wufu ; Wei, Xiongpiao ; An, Yufeng ; Huang, Xiaoling ; Wang, Linxiao ; Tu, Yuanbiao ; Qiao, Lukai

Recently, some studies have proven that AXL plays a crucial role in the drug resistance of tumors. At present, no AXL inhibitors on the market and it is essential to discover novel compounds targeting AXL to overcome resistance. In this work, based on the anchor structure, 21,313 compounds were obtained by substructure search from more than 400,000 compounds. Then, the Qvina and Ledock were selected for virtual screening to obtain 17 compounds. Next, four compounds (ARRY614, AMI-1, NG25, and Butein) were selected for bioactivity evaluation after hydrogen bond and cluster analysis. Further activity evaluation suggested that the compound AMI-1 is a novel AXL inhibitor with an IC₅₀ value of 1.13 uM. In addition, molecular dynamics simulation demonstrated that compound AMI-1 contained lower binding energy and more key residues than the other three compounds, showing the best inhibitory activity against AXL. Finally, further MM/PBSA prediction showed that AMI-1 is more sensitive to mutant protein 3IKA than wildtype protein 1M17, which means that the AMI-1 may be helpful to overcome the resistance of EGFR^T790M mutations. In conclusion, this work successfully discovered a novel compound with moderate inhibitory activity against AXL by a drug discovery workflow, which also could be applied to discover active compounds for other targets quickly.Communicated by Ramaswamy H. Sarma.

01 Aug 2024·Leukemia

Repurposing pexmetinib as an inhibitor of TKI-resistant BCR::ABL1

Letter

Author: Villa, Matteo ; Malighetti, Federica ; Gambacorti-Passerini, Carlo ; Mologni, Luca ; Fontana, Diletta ; Zambon, Alfonso

19 Aug 2023·Research square

Tumor cell p38 inhibition to overcome immunotherapy resistance.

Author: Smith, Katelyn ; Deitrick, Christopher ; Reeder, Carly ; Sellitto, Lorenzo ; Luke, Jason J ; Zandberg, Dan P ; Christner, Susan M ; Kulkarni, Aditi ; Bruno, Tullia C ; Behr, Sarah ; Dadey, Rebekah E ; Li, Aofei ; Poklepovic, Andrew S ; Vujanović, Lazar ; Soloff, Adam C ; Newman, Sarah ; Bao, Riyue ; Villaruz, Liza C ; Doerfler, Rose ; Urban, Julie ; Singh, Krishna B ; Joy, Marion ; Beumer, Jan H ; Augustin, Ryan C ; Skinner, Heath D ; Isett, Brian ; Ferris, Robert L ; Jelinek, Mark ; Najjar, Yana ; Davar, Diwakar ; Lee, Patrice

Patients with tumors that do not respond to immune-checkpoint inhibition often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-γ-associated CD8⁺ T cell and dendritic cell activation. Understanding the molecular mechanisms underlying immune exclusion in non-responding patients may enable the development of novel combination therapies. p38 MAPK is a known regulator of dendritic and myeloid cells however a tumor-intrinsic immunomodulatory role has not been previously described. Here we identify tumor cell p38 signaling as a therapeutic target to potentiate anti-tumor immunity and overcome resistance to immune-checkpoint inhibitors (ICI). Molecular analysis of tumor tissues from patients with human papillomavirus-negative head and neck squamous carcinoma reveals a p38-centered network enriched in non-T cell-inflamed tumors. Pan-cancer single-cell RNA analysis suggests that p38 activation may be an immune-exclusion mechanism across multiple tumor types. P38 knockdown in cancer cell lines increases T cell migration, and p38 inhibition plus ICI in preclinical models shows greater efficacy compared to monotherapies. In a clinical trial of patients refractory to PD1/L1 therapy, pexmetinib, a p38 inhibitor, plus nivolumab demonstrated deep and durable clinical responses. Targeting of p38 with anti-PD1 has the potential to induce the T cell-inflamed phenotype and overcome immunotherapy resistance.

100 Deals associated with Pexmetinib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16294

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	US	Array BioPharma, Inc.	11 Jun 2020
Melanoma	Phase 2	US	Array BioPharma, Inc.	11 Jun 2020
Non-Small Cell Lung Cancer	Phase 2	US	Array BioPharma, Inc.	11 Jun 2020
Renal Cell Carcinoma	Phase 2	US	Array BioPharma, Inc.	11 Jun 2020
Squamous Cell Carcinoma of Head and Neck	Phase 2	US	Array BioPharma, Inc.	11 Jun 2020
Myelodysplastic Syndromes	Preclinical	US	Array BioPharma, Inc.	01 Jun 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04074967 (SITC2022) Manual	Phase 1	HR-positive/HER2-low Solid Tumors Last line	28	Nivolumab+ARRY-614	(zajntzsplc) = The RP2D is 200 mg ARRY-614 with ICB ehynereupb (syplgszwpm ) View more	Positive	01 Nov 2022
NCT04074967 (SITC2022) Manual	Phase 1	HR-positive/HER2-low Solid Tumors Last line	28	Ipilimumab+ARRY-614		Positive	01 Nov 2022
NCT00916227 (Pubmed \| Clin Cancer Res) Manual	Phase 1	Myelodysplastic Syndromes	44	ARRY-614	(mjchlmrzyt) = NR( for once daily dosing)；300 mg twice daily schedule was not tolerated aihhbgtboe (jxttizoikv ) View more	Positive	01 Mar 2015