Delving into the Latest Updates on ASP-3026 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

ASP 3026

Target

ALK

Action

inhibitors

Mechanism

ALK inhibitors(Anaplastic lymphoma kinase inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesNervous System Diseases+ [1]

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmB-Cell LymphomaBrain metastases

Originator Organization

Astellas Pharma, Inc.

Active Organization-

Inactive Organization

Astellas Pharma, Inc.

License Organization-

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC29H40N8O3S

InChIKeyMGGBYMDAPCCKCT-UHFFFAOYSA-N

CAS Registry1097917-15-1

Anaplastic lymphoma kinase (ALK) inhibitor crizotinib has dramatic effect in non-small cell lung cancer patients with ALK rearrangement. However, most patients eventually develop resistance. To discover therapeutic targets to overcome crizotinib resistance (CR), we generated patient-derived xenograft CR mice and subjected them to phosphorylation profiling, together with CR mice treated with ASP3026 or alectinib. We identified 100 proteins with different phosphorylation status in CR mice. Among them, AXL phosphorylation was increased in CR mice, which could not be reversed by ASP3026 or alectinib. Importantly, the combined treatment of crizotinib and AXL inhibitor in CR mice significantly inhibited tumor growth, compared to crizotinib alone. We also found that SHC1 phosphorylation was increased in CR mice and SHC1 knockdown sensitized ALK-driven cells to crizotinib. Our study provides a new view of signaling pathways leading to CR, suggesting AXL and SHC1 as potential targets for combination therapy to overcome CR.

01 Aug 2021·Cell reportsQ1 · BIOLOGY

NGPF2 triggers synaptic scaling up through ALK-LIMK-cofilin-mediated mechanisms

Q1 · BIOLOGY

ArticleOA

Author: Han, Lifang ; Yu, Shunying ; Xia, Shuting ; Dang, Rui ; Lv, Xin ; Zhang, Xiaolin ; Zhou, Zikai ; Meng, Yanghong ; He, Guiqin ; Jia, Zhengping ; Liu, An ; Qi, Junxia ; Zhang, Xiaoyun ; Xie, Wei ; Xie, Hao

Synaptic scaling is an extensively studied form of homeostatic plasticity critically involved in various brain functions. Although it is accepted that synaptic scaling is expressed through the postsynaptic accumulation of AMPA receptors (AMPARs), the induction mechanism remains elusive. In this study, we show that TTX treatment induces rapid but transient release of the neurite growth-promoting factor 2 (NGPF2), and this release is necessary and sufficient for TTX-induced scaling up. In addition, we show that inhibition of the anaplastic lymphoma kinase (ALK)-LIMK-cofilin signaling pathway blocks TTX- and NGPF2-induced synaptic scaling up. Furthermore, we show that TTX-induced release of NGPF2 is protein synthesis dependent and requires fragile X mental retardation protein 1 (FMRP1). These results indicate that activity blockade induces NGPF2 synthesis and release to trigger synaptic scaling up through LIMK-cofilin-dependent actin reorganization, spine enlargement, and stabilization of AMPARs at the synapse.

01 Mar 2021·Drugs in R&DQ4 · MEDICINE

Safety and Antitumor Activity of Repeated ASP3026 Administration in Japanese Patients with Solid Tumors: A Phase I Study

Q4 · MEDICINE

ArticleOA

Author: Takeda, Kentaro ; Morita, Satoshi ; Shimizu, Toshio ; Murakami, Haruyasu ; Fukuoka, Masahiro ; Takeshita, Shigeru ; Nakagawa, Kazuhiko ; Ono, Akira ; Morishita, Maiko ; Seto, Takashi ; Nagase, Itsuro ; Bahceci, Erkut ; Toyoshima, Junko ; Watanabe, Sawori

BACKGROUND AND OBJECTIVE:

Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required.

METHODS:

This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts.

RESULTS:

Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group).

CONCLUSION:

ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile.

CLINICAL TRIAL REGISTRATION:

This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.

100 Deals associated with ASP-3026

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12729

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	Japan	Astellas Pharma, Inc.	01 May 2011
B-Cell Lymphoma	Phase 1	United States	Astellas Pharma, Inc.	01 Dec 2010
Brain metastases	Phase 1	United States	Astellas Pharma, Inc.	01 Dec 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01401504 (Pubmed \| Drugs R D)	Phase 1	Solid tumor	29	ASP3026	knqdaxuodp(zjhrqiwmia) = ezlojisqkg tupduwwhle (yruvdibuje )	-	17 Dec 2020
NCT01284192 (Pubmed \| J Hematol Oncol) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	46	ASP3026	ksyhbsqejp(dkfxcbmssl) = nausea 38%, fatigue 35%, and vomiting 35 % ignnkbzmbs (emrqbjqivl )	Positive	10 Mar 2016
NCT01401504 (ASCO2014)	Phase 1	ALK-positive anaplastic large cell lymphoma	46	ASP3026	bryfxtyncb(skdcuzqjvb) = mochdnwgeo dpzcccdqli (loojyejscs ) View more	-	20 May 2014
NCT01401504 (ASCO2013)	Phase 1	Solid tumor	30	ASP3026	xyelzfzvtu(hqldpyngvb) = vhsvrdcwmu qgxmqqmxde (ipxlaslngm ) View more	-	20 May 2013