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(Synonyms: (6-(1-((6-甲氧基吡啶-3-基)甲基)哌啶-4-基)-1H-苯并[D]咪唑-2-基)(4-(4-(三氟甲基)苄基)哌嗪-1-基)甲酮双对甲苯磺酸盐) 目录号 : GC60058

ASP4132 is a potent and orally active activator of Adenosine Monophosphate-Activated Protein Kinase (AMPK) with EC50 of 0.018 μM. ASP4132 is used as a clinical candidate for the treatment of human cancer.

ASP4132 Chemical Structure

Cas No.:1640294-30-9

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10mM (in 1mL DMSO)
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5mg
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产品描述

ASP4132 is a potent and orally active activator of Adenosine Monophosphate-Activated Protein Kinase (AMPK) with EC50 of 0.018 μM. ASP4132 is used as a clinical candidate for the treatment of human cancer.

ASP4132 is a new type of AMPK activator with potent AMPK activation activity and attractive selective growth inhibition against human cancer cells, improves aqueous solubility, metabolic stability and animal pharmacokinetics (PK). Studies on ASP4132 have advanced to clinical trials for the treatment of cancer.[1]

The in vivo efficacy of ASP4132 is evaluated via MDA-MB-453 xenografts in nude mice. The tumor growth inhibition (TGI) rate is 29% at 1 mg/kg (p.o.), and the tumor regression rate is 26%, 87% and 96% at 2, 4 and 8 mg/kg, respectively. All doses of ASP4132 are well tolerated over the 21-day dosing window, and no body weight loss is observed.[1]

[1] Kazuyuki Kuramoto, et al. Bioorg Med Chem. 2020 Mar 1;28(5):115307.

Chemical Properties

Cas No. 1640294-30-9 SDF
别名 (6-(1-((6-甲氧基吡啶-3-基)甲基)哌啶-4-基)-1H-苯并[D]咪唑-2-基)(4-(4-(三氟甲基)苄基)哌嗪-1-基)甲酮双对甲苯磺酸盐
Canonical SMILES O=C(C1=NC2=CC=C(C3CCN(CC4=CC=C(OC)N=C4)CC3)C=C2N1)N5CCN(CC6=CC=C(C(F)(F)F)C=C6)CC5.O=S(C7=CC=C(C)C=C7)(O)=O.O=S(C8=CC=C(C)C=C8)(O)=O
分子式 C46H51F3N6O8S2 分子量 937.06
溶解度 DMSO: 250 mg/mL (266.79 mM); Methanol: 8.33 mg/mL (8.89 mM) 储存条件 Store at -20°C
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1 mM 1.0672 mL 5.3358 mL 10.6717 mL
5 mM 0.2134 mL 1.0672 mL 2.1343 mL
10 mM 0.1067 mL 0.5336 mL 1.0672 mL
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Research Update

AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth

Cell Death Dis 2021 Apr 6;12(4):365.PMID:33824293DOI:10.1038/s41419-021-03655-2.

Activation of adenosine monophosphate-activated protein kinase (AMPK) is able to produce significant anti-non-small cell lung cancer (NSCLC) cell activity. ASP4132 is an orally active and highly effective AMPK activator. The current study tested its activity against NSCLC cells. In primary NSCLC cells and established cell lines (A549 and NCI-H1944) ASP4132 potently inhibited cell growth, proliferation and cell cycle progression as well as cell migration and invasion. Robust apoptosis activation was detected in ASP4132-treated NSCLC cells. Furthermore, ASP4132 treatment in NSCLC cells induced programmed necrosis, causing mitochondrial p53-cyclophilin D (CyPD)-adenine nucleotide translocase 1 (ANT1) association, mitochondrial depolarization and medium lactate dehydrogenase release. In NSCLC cells ASP4132 activated AMPK signaling, induced AMPKα1-ACC phosphorylation and increased AMPK activity. Furthermore, AMPK downstream events, including mTORC1 inhibition, receptor tyrosine kinases (PDGFRα and EGFR) degradation, Akt inhibition and autophagy induction, were detected in ASP4132-treated NSCLC cells. Importantly, AMPK inactivation by AMPKα1 shRNA, knockout (using CRISPR/Cas9 strategy) or dominant negative mutation (T172A) almost reversed ASP4132-induced anti-NSCLC cell activity. Conversely, a constitutively active AMPKα1 (T172D) mimicked and abolished ASP4132-induced actions in NSCLC cells. In vivo, oral administration of a single dose of ASP4132 largely inhibited NSCLC xenograft growth in SCID mice. AMPK activation, mTORC1 inhibition and EGFR-PDGFRα degradation as well as Akt inhibition and autophagy induction were detected in ASP4132-treated NSCLC xenograft tumor tissues. Together, activation of AMPK by ASP4132 potently inhibits NSCLC cell growth in vitro and in vivo.

First-in-human evaluation of the novel mitochondrial complex I inhibitor ASP4132 for treatment of cancer

Invest New Drugs 2021 Oct;39(5):1348-1356.PMID:33830407DOI:10.1007/s10637-021-01112-7.

Background We assessed the safety, tolerability, and pharmacokinetics of mitochondrial complex 1 inhibitor ASP4132. Methods This phase I dose-escalation/dose-expansion study enrolled patients with treatment refractory advanced solid tumors to assess safety, dose-limiting toxicities (DLTs), efficacy and pharmacokinetic or oral ASP4132. Results Overall, 39 patients received ASP4132. Acceptable tolerability of ASP4132 5 mg in the first patient led to enrollment in the 10-mg dose cohort. After two DLTs at the 10-mg dose, additional patients were enrolled in the 5-mg cohort; a 7.5-mg cohort and two intermittent-dosing cohorts (ASP4132 10 mg for 3 days, then 4 days off; ASP4132 15 mg for 1 day, then 6 days off). ASP4132 5 mg was well tolerated; however, multiple DLTs such as fatigue, mental status changes, dizziness, lactic acidosis, enteritis, and posterior reversible encephalopathy syndrome were observed in higher dose cohorts (7.5-mg and intermittent 10-mg and 15-mg dose cohorts). Stable disease (+ 4 % to + 15 %) was observed in 8/39 (20.5 %) patients. ASP4132 plasma pharmacokinetics were characterized by high variability, with rapid absorption and accumulation from slow elimination. Conclusions ASP4132 showed limited clinical activity, and DLTs prohibited dose escalation. Further research is required to determine if DLTs will limit clinical activity of other mitochondrial complex I inhibitors. Clinical Trial ID (clinicaltrials.gov): NCT02383368, March 9, 2015.

Development of a potent and orally active activator of adenosine monophosphate-activated protein kinase (AMPK), ASP4132, as a clinical candidate for the treatment of human cancer

Bioorg Med Chem 2020 Mar 1;28(5):115307.PMID:32007387DOI:10.1016/j.bmc.2020.115307.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a key role in maintaining cellular metabolism. AMP or adenosine diphosphate (ADP) levels rise during metabolic stress, such as during nutrient starvation, hypoxia and muscle contraction, and bind to AMPK to induce activity. Recently, activation of AMPK has been considered an attractive therapeutic strategy in the field of human oncology. Structural optimization of lead compound 2, a new type of AMPK activator with potent AMPK activation activity and attractive selective growth inhibition against human cancer cells, improved aqueous solubility, metabolic stability and animal pharmacokinetics (PK) and culminated in the identification of (5-{1-[(6-methoxypyridin-3-yl)methyl]piperidin-4-yl}-1H-benzimidazol-2-yl)(4-{[4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)methanone ditosylate, ASP4132 (28). Studies on ASP4132 had advanced to clinical trials for the treatment of cancer.

Novel Indirect AMP-Activated Protein Kinase Activators: Identification of a Second-Generation Clinical Candidate with Improved Physicochemical Properties and Reduced hERG Inhibitory Activity

Chem Pharm Bull (Tokyo) 2020;68(5):452-465.PMID:32378543DOI:10.1248/cpb.c20-00015.

This study reports the synthesis and evaluation of novel indirect AMP-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. We performed back-up medicinal chemistry synthetic research on ASP4132, a previously reported as a compound for clinical development that acts as an indirect AMPK activator. This led to the successful identification of 4-({4-[5-({1-[(5-ethoxypyrazin-2-yl)methyl]-4-fluoropiperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piperazin-1-yl}methyl)benzonitrile succinate (27b), a potent, highly aqueous soluble and metabolically stable compound in human hepatocytes. Compound 27b also showed weaker human Ether-a-go-go Related Gene (hERG) inhibitory activity than that of compound 13 and ASP4132. Therefore, 27b was a promising AMPK activator and a second-generation clinical candidate for treatment for human cancer.