Asciminib free base | ABL001 | CAS#1492952-76-7 | BCR-ABL inhibitor

MedKoo Cat#: 206490 | Name: Asciminib free base

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Asciminib, also known as ABL001, is a potent allosteric inhibitor of BCR-ABL. ABL001 prevents emergence of resistant disease when administered in combination with nilotinib in an in vivo murine model of chronic myeloid leukemia. Cell proliferation studies demonstrate that ABL001 selectively inhibited the growth of CML and Ph+ ALL cells with potencies ranging from 1-10nM range. ABL001 was tested for activity against clinically observed mutations and found to be active in the low nM range. In the KCL-22 mouse xenograft model, ABL001 displayed potent anti-tumor activity with complete tumor regression observed and a clear dose-dependent correlation with pSTAT5 inhibition.

Chemical Structure

Asciminib free base

CAS#1492952-76-7 (free base)

Theoretical Analysis

MedKoo Cat#: 206490

Name: Asciminib free base

CAS#: 1492952-76-7 (free base)

Chemical Formula: C20H18ClF2N5O3

Exact Mass: 449.1066

Molecular Weight: 449.84

Elemental Analysis: C, 53.40; H, 4.03; Cl, 7.88; F, 8.45; N, 15.57; O, 10.67

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 310.00	Ready to ship
50mg	USD 550.00	Ready to ship
100mg	USD 950.00	Ready to ship
200mg	USD 1,450.00	Ready to ship
500mg	USD 2,850.00	Ready to ship
1g	USD 4,250.00	Ready to ship
2g	USD 6,850.00	2 Weeks

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Related CAS #

1492952-76-7 (free base) 2119669-71-3 (HCl)

Synonym

ABL-001; AB -001; ABL001; asciminib; asciminib free base;

IUPAC/Chemical Name

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide

InChi Key

VOVZXURTCKPRDQ-CQSZACIVSA-N

InChi Code

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

SMILES Code

O=C(NC1=CC=C(OC(F)(Cl)F)C=C1)C2=CN=C(N3C[C@H](O)CC3)C(C4=CC=NN4)=C2

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot# A20T10K13

View CoA: current batch, Lot#A20T12K08

QC Data

View QC data: current batch, Lot#A20T10K13

View QC data: current batch, Lot#A20T12K08

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Asciminib (ABL001) is a potent and selective allosteric BCR-ABL1 inhibitor, which inhibits Ba/F3 cells grown with an IC50 of 0.25 nM.

In vitro activity:

A clinically used ferto-protective drug should not interfere with the therapeutic effect of DNA-damaging chemotherapies. This assumption was validated by assessing the effect of Asciminib on 4-hydroperoxy-cyclophosphamide (4-OH-Cy)-treated MCF7 breast tumor cells. These results demonstrate that the co-treatment with Asciminib did not affect 4-OH-Cy-induced phosphorylation of DDR marker proteins like ATM, γH2AX, or p53 (Figure 4A). Additionally, single-cell gel electrophoresis (Comet) assays revealed that Asciminib did not interfere with the DNA-damaging effect of 4-OH-Cy (Figure 4B). Finally, the co-administration of Asciminib did not affect the cytotoxic effect of 4-OH-Cy (Figure 4C). Taken together, these data support the potential use of Asciminib as a fertoprotective drug without abrogating the cytotoxic effect of 4-OH-CY. Reference: Int J Mol Sci. 2021 Feb; 22(3): 1395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866503/

In vivo activity:

Next, P7 mice were injected with Cy alone (100 mg/kg) or in combination with increasing concentrations of Asciminib (0.1, 0.2, and 0.5 mg/kg, respectively). Co-treatment with Asciminib resulted in partial inhibition of TAp63 modification (commonly observed as a shift of TAp63 protein according to W.B. assay). In Figure 2A, a partial prevention of TAp63 shift (see yellow arrows) was observed 18 h after co-injection with Cy and Asciminib. The phosphorylation of histone H2AX was observed at Ser139 (γH2AX), an early marker of DDR in the ovarian lysates. To assess if Asciminib affects DDR activation in primordial/primary oocytes, the phosphorylation of DDR sentinel proteins were monitored using IF assays performed on ovarian sections. It was found that Asciminib attenuated DNA stress signaling induced by Cy in the ovarian reserve. Co-treated ovaries exhibited reduced staining for phosphoDNA-PK, γH2AX, and cleaved PARP in the nuclei of reserve oocytes (Figure 2B–D).Taken together, these data demonstrate that Asciminib can affect both of these signaling pathways activated by Cy in the ovary. Reference: Int J Mol Sci. 2021 Feb; 22(3): 1395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866503/

	Solvent	mg/mL	mM
Solubility
	DMSO	93.0	206.74
	Ethanol	90.0	200.07

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 449.84 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Mattiello L, Pucci G, Marchetti F, Diederich M, Gonfloni S. Asciminib Mitigates DNA Damage Stress Signaling Induced by Cyclophosphamide in the Ovary. Int J Mol Sci. 2021 Jan 30;22(3):1395. doi: 10.3390/ijms22031395. PMID: 33573271; PMCID: PMC7866503. 2. Eadie LN, Saunders VA, Branford S, White DL, Hughes TP. The new allosteric inhibitor asciminib is susceptible to resistance mediated by ABCB1 and ABCG2 overexpression in vitro. Oncotarget. 2018 Feb 3;9(17):13423-13437. doi: 10.18632/oncotarget.24393. PMID: 29568367; PMCID: PMC5862588.

In vitro protocol:

In vivo protocol:

1: Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, Breccia M, Goh YT, Talpaz M, Hochhaus A, le Coutre P, Ottmann O, Heinrich MC, Steegmann JL, Deininger MWN, Janssen JJWM, Mahon FX, Minami Y, Yeung D, Ross DM, Tallman MS, Park JH, Druker BJ, Hynds D, Duan Y, Meille C, Hourcade-Potelleret F, Vanasse KG, Lang F, Kim DW. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019 Dec 12;381(24):2315-2326. doi: 10.1056/NEJMoa1902328. PMID: 31826340; PMCID: PMC7724923. 2: Shanmuganathan N, Hughes TP. Asciminib for chronic myeloid leukaemia: Next questions. Br J Haematol. 2022 Nov;199(3):322-331. doi: 10.1111/bjh.18323. Epub 2022 Jun 21. PMID: 35729850. 3: Réa D, Mauro MJ, Boquimpani C, Minami Y, Lomaia E, Voloshin S, Turkina A, Kim DW, Apperley JF, Abdo A, Fogliatto LM, Kim DDH, le Coutre P, Saussele S, Annunziata M, Hughes TP, Chaudhri N, Sasaki K, Chee L, García-Gutiérrez V, Cortes JE, Aimone P, Allepuz A, Quenet S, Bédoucha V, Hochhaus A. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021 Nov 25;138(21):2031-2041. doi: 10.1182/blood.2020009984. PMID: 34407542; PMCID: PMC9728405. 4: Deeks ED. Asciminib: First Approval. Drugs. 2022 Feb;82(2):219-226. doi: 10.1007/s40265-021-01662-3. PMID: 35041175. 5: Réa D, Hughes TP. Development of asciminib, a novel allosteric inhibitor of BCR-ABL1. Crit Rev Oncol Hematol. 2022 Mar;171:103580. doi: 10.1016/j.critrevonc.2022.103580. Epub 2022 Jan 10. PMID: 35021069. 6: Assanto GM, Scalzulli E, Breccia M. Asciminib in chronic myeloid leukemia. Drugs Today (Barc). 2022 Oct;58(10):479-489. doi: 10.1358/dot.2022.58.10.3441853. PMID: 36305542. 7: Asciminib for chronic myeloid leukaemia. Aust Prescr. 2022 Dec;45(6):211-212. doi: 10.18773/austprescr.2022.070. Epub 2022 Oct 12. PMID: 36479334; PMCID: PMC9722350. 8: Manley PW, Barys L, Cowan-Jacob SW. 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. 2020 Nov;98:106458. doi: 10.1016/j.leukres.2020.106458. Epub 2020 Sep 29. PMID: 33096322. 9: Gleixner KV, Filik Y, Berger D, Schewzik C, Stefanzl G, Sadovnik I, Degenfeld-Schonburg L, Eisenwort G, Schneeweiss-Gleixner M, Byrgazov K, Sperr WR, Mayer J, Lion T, Valent P. Asciminib and ponatinib exert synergistic anti- neoplastic effects on CML cells expressing BCR- ABL1T315I-compound mutations. Am J Cancer Res. 2021 Sep 15;11(9):4470-4484. PMID: 34659899; PMCID: PMC8493398. 10: Yeung DT, Shanmuganathan N, Hughes TP. Asciminib: a new therapeutic option in chronic-phase CML with treatment failure. Blood. 2022 Jun 16;139(24):3474-3479. doi: 10.1182/blood.2021014689. PMID: 35468180. 11: Zerbit J, Tamburini J, Goldwirt L, Decroocq J, Cayuela JM, Chapuis N, Contejean A, Batista R, Bouscary D, Willems L. Asciminib and ponatinib combination in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leuk Lymphoma. 2021 Dec;62(14):3558-3560. doi: 10.1080/10428194.2021.1966787. Epub 2021 Aug 18. PMID: 34405773. 12: Asciminib Hydrochloride. Am J Health Syst Pharm. 2022 Feb 8;79(4):207-210. doi: 10.1093/ajhp/zxab437. PMID: 35024798. 13: Hochhaus A, Réa D, Boquimpani C, Minami Y, Cortes JE, Hughes TP, Apperley JF, Lomaia E, Voloshin S, Turkina A, Kim DW, Abdo A, Fogliatto LM, le Coutre P, Sasaki K, Kim DDH, Saussele S, Annunziata M, Chaudhri N, Chee L, García- Gutiérrez V, Kapoor S, Allepuz A, Quenet S, Bédoucha V, Mauro MJ. Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. Leukemia. 2023 Mar;37(3):617-626. doi: 10.1038/s41375-023-01829-9. Epub 2023 Jan 30. PMID: 36717654; PMCID: PMC9991909. 14: Hoch M, Zack J, Quinlan M, Huth F, Forte S, Dodd S, Aimone P, Hourcade- Potelleret F. Pharmacokinetics of Asciminib When Taken With Imatinib or With Food. Clin Pharmacol Drug Dev. 2022 Feb;11(2):207-219. doi: 10.1002/cpdd.1019. Epub 2021 Oct 5. PMID: 34609077. 15: Breccia M, Colafigli G, Scalzulli E, Martelli M. Asciminib: an investigational agent for the treatment of chronic myeloid leukemia. Expert Opin Investig Drugs. 2021 Aug;30(8):803-811. doi: 10.1080/13543784.2021.1941863. Epub 2021 Jun 24. PMID: 34130563. 16: Choi EJ. Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase. Blood Res. 2023 Apr 30;58(S1):S29-S36. doi: 10.5045/br.2023.2023017. Epub 2023 Mar 9. PMID: 36891575; PMCID: PMC10133857. 17: Cortes JE, Hochhaus A, Takahashi N, Larson RA, Issa GC, Bombaci F, Ramscar N, Ifrah S, Hughes TP. Asciminib monotherapy for newly diagnosed chronic myeloid leukemia in chronic phase: the ASC4FIRST phase III trial. Future Oncol. 2022 Dec;18(38):4161-4170. doi: 10.2217/fon-2022-0923. Epub 2022 Dec 16. PMID: 36524980. 18: García-Gutiérrez V, Hernandez-Boluda JC. An evaluation of asciminib for patients with chronic myeloid leukemia previously treated with ≥2 tyrosine kinase inhibitors. Expert Rev Hematol. 2022 Jun;15(6):477-484. doi: 10.1080/17474086.2022.2080049. Epub 2022 May 30. PMID: 35583386. 19: Eide CA, Zabriskie MS, Savage Stevens SL, Antelope O, Vellore NA, Than H, Schultz AR, Clair P, Bowler AD, Pomicter AD, Yan D, Senina AV, Qiang W, Kelley TW, Szankasi P, Heinrich MC, Tyner JW, Rea D, Cayuela JM, Kim DW, Tognon CE, O'Hare T, Druker BJ, Deininger MW. Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants. Cancer Cell. 2019 Oct 14;36(4):431-443.e5. doi: 10.1016/j.ccell.2019.08.004. Epub 2019 Sep 19. PMID: 31543464; PMCID: PMC6893878. 20: Schiffer CA. Asciminib for CML: same target, new arrow. Blood. 2021 Nov 25;138(21):2009-2010. doi: 10.1182/blood.2021013257. PMID: 34821938.