Asciminib

Size	Price	Stock	Quantity
10 mg	$259	In stock

Solubility

Soluble in DMSO.

Application

Tyrosine Kinase Inhibitors

Storage

Store in a cool and dry place (or refer to the Certificate of Analysis).

IUPACName

N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

Synonyms

ABL-001; ABL 001; ABL001; N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

InChI Key

VOVZXURTCKPRDQ-CQSZACIVSA-N

InChI

InChI=1S/C20H18ClF2N5O3/c21-20(22,23)31-15-3-1-13(2-4-15)26-19(30)12-9-16(17-5-7-25-27-17)18(24-10-12)28-8-6-14(29)11-28/h1-5,7,9-10,14,29H,6,8,11H2,(H,25,27)(H,26,30)/t14-/m1/s1

Canonical SMILES

C1CN(CC1O)C2=NC=C(C=C2C3=CC=NN3)C(=O)NC4=CC=C(C=C4)OC(F)(F)Cl

1.Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: safety and efficacy.

Massaro F;Colafigli G;Molica M;Breccia M Expert Rev Hematol. 2018 Apr;11(4):301-306. doi: 10.1080/17474086.2018.1451322. Epub 2018 Mar 13.

Chronic myeloid leukemia (CML) is characterized by a pathognomonic chromosomal translocation, which leads to the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus 1 (ABL1) genes, generating an oncoprotein with deregulated tyrosine kinase activity. Areas covered: In the last two decades, BCR/ABL1 kinase has become the molecular target for tyrosine kinase inhibitors (TKIs), a class of drugs that impressively improved overall survival. Despite these results, a proportion of patients experiences resistance to TKIs and need to change treatment. Furthermore, TKIs are unable to eradicate leukemic stem cells, allowing the persistence of neoplastic clones. Therefore, there is still clinical need for new agents to overcome common resistance mechanisms to available drugs. This review explores the horizon of drugs actually under investigation for CML patients resistant to conventional treatment. Expert commentary: Radotinib is an ATP-competitive TKI that showed significant activity also in front-line setting and could find employment indications in CML. Asciminib, an allosteric ABL1 inhibitor, could demonstrate a higher capacity in overcoming common TKIs resistant mutations, including T315I, but clinical findings are needed.

2.The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.

Wylie AA;Schoepfer J;Jahnke W;Cowan-Jacob SW;Loo A;Furet P;Marzinzik AL;Pelle X;Donovan J;Zhu W;Buonamici S;Hassan AQ;Lombardo F;Iyer V;Palmer M;Berellini G;Dodd S;Thohan S;Bitter H;Branford S;Ross DM;Hughes TP;Petruzzelli L;Vanasse KG;Warmuth M;Hofmann F;Keen NJ;Sellers WR Nature. 2017 Mar 30;543(7647):733-737. doi: 10.1038/nature21702. Epub 2017 Mar 22.

Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph;+;) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib.

3.Second line small molecule therapy options for treating chronic myeloid leukemia.

Molica M;Massaro F;Breccia M Expert Opin Pharmacother. 2017 Jan;18(1):57-65. doi: 10.1080/14656566.2016.1267141. Epub 2016 Dec 9.

Approximately 33% of chronic myeloid leukemia (CML) patients discontinue treatment with imatinib in the long-term due to resistance and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) have added complexity to the treatment paradigm for this disease. Areas covered: Second generation TKIs, approved as second-line treatment in all phases of the disease, are highly effective in patients resistant to and/or intolerant to imatinib and are extremely active against all the resistant BCR-ABL1 mutations, with the exception of T3151. Ponatinib, active against all BCR-ABL1 mutants including T315I, became widely used for resistant patients in all phases of disease after previous therapies. Other drugs, such as ABL001, which targets the myristoyl pocket of the ABL1 kinase, are currently in development, to offer therapeutic alternatives for resistant patients to ATP-binders. Expert opinion: In this review, we summarize the efficacy of second line small molecules available. Specific safety profiles have emerged for each drug from sponsored clinical trials in the long-term. Stratification of patients according to comorbidities and cardiovascular risk is now needed to individualize second line treatment.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
1 mM	2.2230 mL	11.1151 mL	22.2301 mL
5 mM	0.4446 mL	2.2230 mL	4.4460 mL
10 mM	0.2223 mL	1.1115 mL	2.2230 mL
50 mM	0.0445 mL	0.2223 mL	0.4446 mL

How does this compound inhibit the expression of Viral protein and mRNA ?

It has a significant inhibitory effect on the expression of proteins after HSV infection and is dose-dependent.

14/7/2016

Hello, can Asciminib be used in vivo?

In mice implanted with KCL-22 tumors, the lowest dose of Asciminib required for complete regression was 7.5 mg/kg twice daily (BID) or 30 mg/kg once daily (QD), and tolerated doses of up to 250 mg/kg. Similarly, in patient-derived xenografts, treatment with 7.5 and 30 mg/kg of Asciminib resulted in persistent regression during administration.

12/12/2017

What is the molecular mechanism by which Asiminib significantly increases the inhibitory activity of Johnny lotinib?

Exploring molecular mechanisms for such allosteric enhancement via systematic computational investigation incorporating molecular dynamics, metadynamics simulations, and density functional theory calculations, we found two distinct contributions. First, binding of Asciminib triggers conformational changes in the inactive state of the protein, thereby making the activation process less favorable by ∼4 kcal/mol. Second, the binding of Asciminib decreases the binding free energies of nilotinib by ∼3 and ∼7 kcal/mol for the wildtype and T315I-mutated protein, respectively.

14/12/2018

Do you have any information on its activity in vitro?

Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without affecting the anticancer potential of cyclophosphamide in vitro.

20/8/2020

what dose can Asciminib completely inhibit the proliferation of HSV ?

Asciminib at 20μmol·L-1 almost completely inhibits HSV proliferation.

1/7/2021

I want to purchase this material. Can I know the Route of sysnthesis ?

Yes. The synthetic routes are as follows: Add TFA (378 mL, 4'910 mmol) to a suspension of N-(4-(chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (87.4 g) in DCM (1.6 L) at 10 °C. Stir the reaction mixture at room temperature for 6 hours. Evaporate off the solvent under reduced pressure. Dissolve the residue in EtOAc (3 L). Wash the residue water (1 L), saturated aqueous NaHCO3 (2 × 1 L) and brine (1 L). Dry the residue over Na2SO4. Evaporate off the solvent under reduced pressure. Purify the residue by chromatography (silica, 2 kg, DCM/MeOH 9:1). Dissolve the crude product in MeOH. Treat the product with Si-thiol (1.3 mmol/g; 10 g, 13 mmol). Stir the reaction mixture at 30 °C for 14 hours. Filter the reaction mixture. Evaporate off the solvent under reduced pressure. Crystallize the residue from MeCN.

19/3/2023

Exhibiting strong activity against HeLa

Asciminib can inhibit the proliferation of HepG2 and cervical cancer cells, particularly exhibiting strong activity against HeLa.That is so incredible.

3/3/2017

anti-proliferative effect

In BCR-ABL1-transformed Ba/F3 cells grown in the absence of IL-3, Asciminib has an good anti-proliferative effect with an IC50 value of 0.25 nM. Working well in the lab.

16/2/2018

An enhancing effect on the antioxidant capacity

In this experiment, we found that Asciminib had an enhancing effect on the antioxidant capacity of the mouse body, which could further enhance immunity and inhibit tumors.

17/7/2018

against all BCR-ABL1 cell lines

Our study showed that Asciminib has selective activity (IC50 value 1-20 nM) against all BCR-ABL1 cell lines, regardless of the presence of p210 or p190 BCR-ABL1 subtypes. Good job.

26/2/2019

inhibit STAT5

In the CML blastostage cell line KCL-22, Asciminib significantly inhibited STAT5 (Tyr694; TYR694; TYR694; TYR694; pSTAT5) and BCR-ABL1 (Tyr245; Phosphorylation of pBCR-ABL1). I’m very happy with the inhibitive effect.

7/7/2019

A significant protective effect on acute lung injury in mice

With significant potential, animal experiments have shown that Asciminib has a significant protective effect on acute lung injury in mice.

8/12/2021

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