Synapse - Global Drug Intelligence Database

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 DisordersHemic and Lymphatic Diseases+ [1]

Active Indication

Colorectal CancerMyelofibrosis

Inactive Indication

Advanced cancerAdvanced Malignant Solid NeoplasmBRAF V600 mutant Colorectal Cancer+ [3]

Originator Organization

Novartis Pharma AG

Active Organization

China Novartis Institutes for BioMedical Research Co., Ltd.Novartis Pharma AG

Inactive Organization

Novartis Pharmaceuticals Corp.

Drug Highest PhaseIND Approval

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC26H27BrF3N5O2

InChIKeyYFCIFWOJYYFDQP-PTWZRHHISA-N

CAS Registry1715025-32-3

Author: Sun, Jong-Mu ; Yang, Jie ; Reguart, Noemi ; Planchard, David ; Couillebault, Xuân-Mai ; Heist, Rebecca S. ; Gaur, Anil ; Min Kim, Tae ; Solomon, Benjamin ; Wolf, Jürgen ; Santoro, Armando ; Sanmamed, Miguel F. ; Sanmamed, Miguel F ; Heist, Rebecca S ; Dooms, Christophe ; Garrido, Pilar ; Mueller, Christina ; Felip, Enriqueta ; Sebastian, Martin ; Bootle, Douglas ; Poggio, Teresa ; Moschetta, Michele ; Wermke, Martin

BACKGROUNDGenetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib.METHODSThis first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics.RESULTSOverall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAF^non-V600-mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively.CONCLUSIONSBoth naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect.CLINICALTRIALSgov identifier: NCT02974725.

Molecular Cancer Therapeutics

Targeted investigational oncology agents in the NCI-60: a phenotypic systems-based resource

Author: Rohrer, Tiffany ; Martin, Karen ; Risbood, Prabhakar ; Williams, John D. ; Lopez, Omar D. ; Wishka, Donn G. ; Ramsey, Patricia ; Evans, David ; White, Stephen L. ; Bowles, Lori ; Sonkin, Dmitriy ; Teicher, Beverly A. ; Morris, Joel ; Grams, Julie ; Polley, Eric C. ; Collins, Jerry M. ; Brady, Penny Sellers ; Doroshow, James H. ; Coussens, Nathan P. ; Dexheimer, Thomas S. ; Kunkel, Mark W.

The NCI-60 human tumor cell line panel has proved to be a useful tool for the global cancer research community in the search for novel chemotherapeutics.The publicly available cell line characterization and compound screening data from the NCI-60 assay have significantly contributed to the understanding of cellular mechanisms targeted by new oncol. agents.Signature sensitivity/resistance patterns generated for a given chemotherapeutic agent against the NCI-60 panel have long served as fingerprint presentations that encompass target information and the mechanism of action associated with the tested agent.We report the establishment of a new public NCI-60 resource based on the cell line screening of a large and growing set of 175 FDA-approved oncol. drugs (AOD) plus >825 clin. and investigational oncol. agents (IOA), representing a diverse set (>250) of therapeutic targets and mechanisms.This data resource is available to the public and includes the raw data from the screening of the IOA and AOD collection along with an extensive set of visualization and anal. tools to allow for comparative study of individual test compounds and multiple compound sets.

Physiological ResearchQ4 · MEDICINE

Introduction to DOK2 and its Potential Role in Cancer

Q4 · MEDICINE

ReviewOA

Author: WANG, Q ; XI, S ; MENG, Y ; PENG, X ; CAI, J ; LI, R ; YANG, X ; SUN, P

Cancer is a complex, multifactorial disease that modern medicine ultimately aims to overcome. Downstream of tyrosine kinase 2 (DOK2) is a well-known tumor suppressor gene, and a member of the downstream protein DOK family of tyrosine kinases. Through a search of original literature indexed in PubMed and other databases, the present review aims to extricate the mechanisms by which DOK2 acts on cancer, thereby identifying more reliable and effective therapeutic targets to promote enhanced methods of cancer prevention and treatment. The review focuses on the role of DOK2 in multiple tumor types in the lungs, intestines, liver, and breast. Additionally, we discuss the potential mechanisms of action of DOK2 and the downstream consequences via the Ras/MPAK/ERK or PI3K/AKT/mTOR signaling pathways.

100 Deals associated with Rineterkib

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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 3	Japan	Novartis Pharmaceuticals Corp.	15 Apr 2016
Advanced Malignant Solid Neoplasm	Phase 3	Switzerland	Novartis Pharmaceuticals Corp.	15 Apr 2016
Advanced Malignant Solid Neoplasm	Phase 3	Spain	Novartis Pharmaceuticals Corp.	15 Apr 2016
Advanced Malignant Solid Neoplasm	Phase 3	Germany	Novartis Pharmaceuticals Corp.	15 Apr 2016
Advanced Malignant Solid Neoplasm	Phase 3	Singapore	Novartis Pharmaceuticals Corp.	15 Apr 2016
Advanced Malignant Solid Neoplasm	Phase 3	United States	Novartis Pharmaceuticals Corp.	15 Apr 2016
Ovarian Cancer	Phase 3	Singapore	Novartis Pharmaceuticals Corp.	15 Apr 2016
Ovarian Cancer	Phase 3	Switzerland	Novartis Pharmaceuticals Corp.	15 Apr 2016
Ovarian Cancer	Phase 3	Japan	Novartis Pharmaceuticals Corp.	15 Apr 2016
Ovarian Cancer	Phase 3	United States	Novartis Pharmaceuticals Corp.	15 Apr 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02974725 (Pubmed \| Lung Cancer) Manual	Phase 1	NRAS Mutant Melanoma \| KRAS mutant Non-small Cell Lung Cancer \| BRAF Mutation Non-small Cell Lung Cancer \| \|	216	Naporafenib + Rineterkib	(hctaiwkdzn) = dyyokhlutj zzdzvaywva (kxfxdmtoop ) View more	Negative	01 Nov 2024
				Naporafenib + Trametinib	(hctaiwkdzn) = kmsbhwzcdu zzdzvaywva (kxfxdmtoop ) View more
NCT04417621 (ESMO2022) Manual	Phase 2	Unresectable Melanoma BRAF V600 Mutation \| NRAS Mutation	133	BRAF V600-mutant	(fexzjefwsi) = kvwolhimor mdbxtencvs (ctyjthjmop, 5 - 25) View more	Positive	10 Sep 2022
				LXH254+LTT462 (BRAF V600-mutant)	(fexzjefwsi) = mumtiezfch mdbxtencvs (ctyjthjmop, 1 - 23) View more
NCT02974725 (ESMO2020)	Phase 1	Non-Small Cell Lung Cancer	49	LXH254 + LTT462	vbpeyqqwiq(ponadhfoyv) = 4% oxldjwccvg (qytnyinbym ) View more	-	17 Sep 2020