asciminib   Click here for help

GtoPdb Ligand ID: 8962

Synonyms: ABL-001 | ABL001 | compound 1 [PMID: 30137981] | Example 9 [1] | Scemblix®
Approved drug PDB Ligand
asciminib is an approved drug (FDA (2021), EMA (2022))
Compound class: Synthetic organic
Comment: Asciminib (ABL001) is a negative allosteric modulator of BCR-ABL1 [1,5,9-10], that induces the kinase to adopt an autoinhibitory, and thereby inactive, conformation [2]. The compound is the result of a structure-guided medicinal chemistry program targeting the vestigial myristoyl pocket of the ABL1 kinase. The acronym STAMP inhibitor is used to descrobe this class of compound, which specifically targets the ABL myristoyl pocket. The structure of ABL001 was disclosed at the American Society of Hematology's (ASH) 57th Annual Meeting and Exposition in Orlando, Florida (Dec., 2015)- see Abstract 1565. Mechanisms by which resistance to asciminib can develop are reported by Qiang et al. (2017) [7], including the development of T315I (confers resistance to ponatinib)-inclusive compound mutations. Combining ponatinib + asciminib has been shown to be effective against such compound mutations [3].
Asciminib-based PROTACs have been reported [11].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 6
Hydrogen bond donors 3
Rotatable bonds 7
Topological polar surface area 103.37
Molecular weight 449.11
XLogP 4.3
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES OC1CCN(C1)c1ncc(cc1c1ccn[nH]1)C(=O)Nc1ccc(cc1)OC(Cl)(F)F
Isomeric SMILES O[C@@H]1CCN(C1)c1ncc(cc1c1ccn[nH]1)C(=O)Nc1ccc(cc1)OC(Cl)(F)F
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
InChI Key VOVZXURTCKPRDQ-CQSZACIVSA-N
References
1. Dodd SK, Furet P, Grotzfeld RM, Jones DB, Manley P, Marizinik A, Pelle XFA, Salem B, Schoepfer J. (2013)
Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1.
Patent number: WO2013171639 A1. Assignee: Novartis Ag.. Priority date: 15/05/2012. Publication date: 21/11/2013.
2. El Rashedy AA, Olotu FA, Soliman MES. (2018)
Dual Drug Targeting of Mutant Bcr-Abl Induces Inactive Conformation: New Strategy for the Treatment of Chronic Myeloid Leukemia and Overcoming Monotherapy Resistance.
Chem Biodivers, 15 (3): e1700533. DOI: 10.1002/cbdv.201700533 [PMID:29325229]
3. Gleixner KV, Filik Y, Berger D, Schewzik C, Stefanzl G, Sadovnik I, Degenfeld-Schonburg L, Eisenwort G, Schneeweiss-Gleixner M, Byrgazov K et al.. (2021)
Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1 T315I-compound mutations.
Am J Cancer Res, 11 (9): 4470-4484. [PMID:34659899]
4. Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, Breccia M, Goh YT, Talpaz M, Hochhaus A et al.. (2019)
Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.
N Engl J Med, 381 (24): 2315-2326. [PMID:31826340]
5. Manley PW, Barys L, Cowan-Jacob SW. (2020)
The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase.
Leuk Res, 98: 106458. [PMID:33096322]
6. Nesr G, Laffan M, Claudiani S, Innes A, Apperley J, Milojkovic D. (2020)
Platelet function in patients with chronic myeloid leukemia treated with asciminib.
Leuk Lymphoma, 61 (12): 3021-3023. [PMID:32654575]
7. Qiang W, Antelope O, Zabriskie MS, Pomicter AD, Vellore NA, Szankasi P, Rea D, Cayuela JM, Kelley TW, Deininger MW et al.. (2017)
Mechanisms of resistance to the BCR-ABL1 allosteric inhibitor asciminib.
Leukemia, 31 (12): 2844-2847. [PMID:28819281]
8. Réa D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E, Voloshin S, Turkina A, Kim DW, Apperley JF, Abdo A et al.. (2021)
A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs.
Blood, 138 (21): 2031-2041. [PMID:34407542]
9. Schoepfer J, Jahnke W, Berellini G, Buonamici S, Cotesta S, Cowan-Jacob SW, Dodd S, Drueckes P, Fabbro D, Gabriel T et al.. (2018)
Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1.
J Med Chem, 61 (18): 8120-8135. [PMID:30137981]
10. Wylie AA, Schoepfer J, Jahnke W, Cowan-Jacob SW, Loo A, Furet P, Marzinzik AL, Pelle X, Donovan J, Zhu W et al.. (2017)
The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.
Nature, 543 (7647): 733-737. [PMID:28329763]
11. Yang Y, Gao H, Sun X, Sun Y, Qiu Y, Weng Q, Rao Y. (2020)
Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects.
J Med Chem, 63 (15): 8567-8583. [PMID:32657579]