Asciminib

Asciminib
Clinical data
Trade names	Scemblix
Other names	ABL001
License data	US DailyMed: Asciminib;
Routes of; administration	By mouth
Drug class	Tyrosine kinase inhibitor
ATC code	L01EA06 (WHO) ;
Legal status
Legal status	US: ℞-only ;
Identifiers
	IUPAC name N-4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide;hydrochloride;
CAS Number	1492952-76-7; as HCl: 2119669-71-3;
PubChem CID	72165228; as HCl: 133082086;
IUPHAR/BPS	8962;
DrugBank	DB12597;
ChemSpider	52085218;
UNII	L1F3R18W77; as HCl: C5U34S9XFV;
KEGG	D11403; as HCl: D11404;
ChEMBL	ChEMBL4208229; as HCl: ChEMBL4297220;
PDB ligand	AY7 (PDBe, RCSB PDB);
Chemical and physical data
Formula	C20H18ClF2N5O3
Molar mass	449.84 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1;
	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; Key:VOVZXURTCKPRDQ-CQSZACIVSA-N;

Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML).^[1]^[2]^[3] Asciminib is a protein kinase inhibitor.^[1]

The most common adverse reactions include upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, and diarrhea.^[2]

Asciminib was approved for medical use in the United States in October 2021.^[1]^[4]^[5]

The U.S. Food and Drug Administration (FDA) granted the application for asciminib priority review, fast track, orphan drug, and breakthrough therapy designations.^[2]^[6]^[7]

Mechanism of action[]

Asciminib is described as a "STAMP inhibitor," which means "specifically targeting the ABL myristoyl pocket." The wild-type ABL has a myristoylated N-terminus, which binds to an allosteric site, but the ABL fusion protein does not have the myristoylated domain. Binding to the allosteric site results in reduced activity for the kinase, thus the fusion protein is constitutively active. Asciminib binds to the allosteric site, resulting in an inhibition of bcr-abl activity.^[8]

Unlike other bcr-abl inhibitors, such as imatinib, asciminib does not bind to the ATP-binding site on the active site of the enzyme. Asciminib and active site bcr-abl inhibitors have non-overlapping resistance mutations. The mutations A337V and P223S overcome the inhibitory activity of asciminib,^[9] but asciminib is not affected by the notorious T315I mutation that affects most ATP-competitive active site inhibitors, except ponatinib.

References[]

^ ^a ^b ^c ^d "Scemblix- asciminib tablet, film coated". DailyMed. Retrieved 4 November 2021.
^ ^a ^b ^c "FDA approves asciminib for Philadelphia chromosome-positive chronic myeloid leukemia". U.S. Food and Drug Administration (FDA) (Press release). 29 October 2021. Retrieved 4 November 2021. This article incorporates text from this source, which is in the public domain.
^ Breccia M, Colafigli G, Scalzulli E, Martelli M (August 2021). "Asciminib: an investigational agent for the treatment of chronic myeloid leukemia". Expert Opinion on Investigational Drugs. 30 (8): 803–811. doi:10.1080/13543784.2021.1941863. PMID 34130563. S2CID 235450899.
^ "Scemblix: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 29 October 2021.
^ "FDA approves Novartis Scemblix (asciminib), with novel mechanism of action for the treatment of chronic myeloid leukemia". Novartis (Press release). Retrieved 29 October 2021.
^ "Asciminib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 27 February 2017. Retrieved 29 October 2021.
^ "Novartis receives FDA Breakthrough Therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia". Novartis (Press release). 8 February 2020. Retrieved 29 October 2021.
^ Schoepfer, Joseph; Jahnke, Wolfgang; Berellini, Giuliano; Buonamici, Silvia; Cotesta, Simona; Cowan-Jacob, Sandra W.; Dodd, Stephanie; Drueckes, Peter; Fabbro, Doriano; Gabriel, Tobias; Groell, Jean-Marc; Grotzfeld, Robert M.; Hassan, A. Quamrul; Henry, Chrystèle; Iyer, Varsha; Jones, Darryl; Lombardo, Franco; Loo, Alice; Manley, Paul W.; Pellé, Xavier; Rummel, Gabriele; Salem, Bahaa; Warmuth, Markus; Wylie, Andrew A.; Zoller, Thomas; Marzinzik, Andreas L.; Furet, Pascal (27 September 2018). "Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1". Journal of Medicinal Chemistry. 61 (18): 8120–8135. doi:10.1021/acs.jmedchem.8b01040. PMID 30137981. S2CID 52073282.
^ Jones, Jill K.; Thompson, Eric M. (September 2020). "Allosteric inhibition of ABL kinases: Therapeutic potential in cancer". Molecular Cancer Therapeutics. 19 (9): 1763–1769. doi:10.1158/1535-7163.MCT-20-0069. PMC 7484003. PMID 32606014.

External links[]

"Asciminib". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02081378 for "A Phase I Study of Oral ABL001 in Patients With CML or Ph+ ALL" at ClinicalTrials.gov
Clinical trial number NCT03106779 for "Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs" at ClinicalTrials.gov

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[Scemblix_FDA_label-1] "Scemblix- asciminib tablet, film coated". DailyMed. Retrieved 4 November 2021.

[FDA_PR_20211029-2] "FDA approves asciminib for Philadelphia chromosome-positive chronic myeloid leukemia". U.S. Food and Drug Administration (FDA) (Press release). 29 October 2021. Retrieved 4 November 2021. This article incorporates text from this source, which is in the public domain.

[Breccia_2021-3] Breccia M, Colafigli G, Scalzulli E, Martelli M (August 2021). "Asciminib: an investigational agent for the treatment of chronic myeloid leukemia". Expert Opinion on Investigational Drugs. 30 (8): 803–811. doi:10.1080/13543784.2021.1941863. PMID 34130563. S2CID 235450899.

[4] "Scemblix: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 29 October 2021.

[5] "FDA approves Novartis Scemblix (asciminib), with novel mechanism of action for the treatment of chronic myeloid leukemia". Novartis (Press release). Retrieved 29 October 2021.

[6] "Asciminib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 27 February 2017. Retrieved 29 October 2021.

[7] "Novartis receives FDA Breakthrough Therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia". Novartis (Press release). 8 February 2020. Retrieved 29 October 2021.

[8] Schoepfer, Joseph; Jahnke, Wolfgang; Berellini, Giuliano; Buonamici, Silvia; Cotesta, Simona; Cowan-Jacob, Sandra W.; Dodd, Stephanie; Drueckes, Peter; Fabbro, Doriano; Gabriel, Tobias; Groell, Jean-Marc; Grotzfeld, Robert M.; Hassan, A. Quamrul; Henry, Chrystèle; Iyer, Varsha; Jones, Darryl; Lombardo, Franco; Loo, Alice; Manley, Paul W.; Pellé, Xavier; Rummel, Gabriele; Salem, Bahaa; Warmuth, Markus; Wylie, Andrew A.; Zoller, Thomas; Marzinzik, Andreas L.; Furet, Pascal (27 September 2018). "Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1". Journal of Medicinal Chemistry. 61 (18): 8120–8135. doi:10.1021/acs.jmedchem.8b01040. PMID 30137981. S2CID 52073282.

[9] Jones, Jill K.; Thompson, Eric M. (September 2020). "Allosteric inhibition of ABL kinases: Therapeutic potential in cancer". Molecular Cancer Therapeutics. 19 (9): 1763–1769. doi:10.1158/1535-7163.MCT-20-0069. PMC 7484003. PMID 32606014.

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