BLU-285 | Avapritinib | CAS#1703793-34-3 | PDGFRα inhibitor

MedKoo Cat#: 206816 | Name: Avapritinib

Description:

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

Avapritinib, also known as BlU-285, is a potent and selective inhibitor of PDGFRα D842V and KIT Exon 17 mutants and is being developed as a highly targeted therapy for SM, a disorder of the mast cells in which a KIT Exon 17 mutation is the primary driver of disease. BLU-285 is currently being developed by Blueprint.

Chemical Structure

Avapritinib

CAS#1703793-34-3

Theoretical Analysis

MedKoo Cat#: 206816

Name: Avapritinib

CAS#: 1703793-34-3

Chemical Formula: C26H27FN10

Exact Mass: 498.2404

Molecular Weight: 498.57

Elemental Analysis: C, 62.64; H, 5.46; F, 3.81; N, 28.09

Price and Availability

Size	Price	Availability
5mg	USD 85.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to Ship
500mg	USD 2,850.00	Ready to Ship
1g	USD 4,250.00	Ready to Ship

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Related CAS #

No Data

Synonym

BLU-285; BLU 285; BLU285, Avapritinib

IUPAC/Chemical Name

(S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine

InChi Key

DWYRIWUZIJHQKQ-SANMLTNESA-N

InChi Code

InChI=1S/C26H27FN10/c1-26(28,20-3-5-22(27)6-4-20)21-13-29-25(30-14-21)36-9-7-35(8-10-36)24-23-11-18(16-37(23)33-17-31-24)19-12-32-34(2)15-19/h3-6,11-17H,7-10,28H2,1-2H3/t26-/m0/s1

SMILES Code

CN1N=CC(C2=CN3C(C(N4CCN(C5=NC=C([C@@](C)(N)C6=CC=C(F)C=C6)C=N5)CC4)=NC=N3)=C2)=C1

Appearance

White to off-white 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

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#T8Z11C26

QC Data

View QC data: current batch, Lot#T8Z11C26

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Avapritinib (BLU-285) is a KIT and PDGFRA activation loop mutant kinases inhibitor with IC50s of 0.27 and 0.24 nM for KIT D816V and PDGFRA D842V, respectively.

In vitro activity:

To evaluate the effect of avapritinib on the drug transport function of ABCB1 and ABCG2, the intracellular accumulation of a known substrate drug of ABCB1 or ABCG2 in the presence or absence of avapritinib in cells expressing ABCB1 or ABCG2 was determined. Avapritinib had no detectable effect on the accumulation of calcein or pheophorbide A (PhA) in drug-sensitive OVCAR-8 human ovarian cancer cells, S1 human colon cancer cells, or parental HEK293 cells (Figure 1A–D, left panels). In contrast, 20 μM avapritinib substantially increased the accumulation of calcein, a fluorescent product of a known ABCB1 substrate drug calcein-AM54 in ABCB1-overexpressing human ovarian cancer cell line NCI-ADR-RES (Figure 1A, right panel) and in MDR19-HEK293 cells (Figure 1B, right panel), which are HEK293 cells transfected with human ABCB1. Similarly, 20 μM avapritinib markedly increased the accumulation of PhA, a fluorescent compound known to be a substrate of ABCG242 in the ABCG2-overexpressing human colon cancer cell line S1-M1–80 (Figure 1C, right panel) and in R482-HEK293 cells (Figure 1D, right panel), which are HEK293 cells transfected with human ABCG2. Reference: Mol Pharm. 2019 Jul 1;16(7):3040-3052. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620786/

In vivo activity:

The activity of avapritinib, a potent and highly selective inhibitor of mutated KIT and PDGFRA, was evaluated in three patient-derived xenograft (PDX) GIST models carrying different KIT mutations, with differential sensitivity to standard TKI. NMRI nu/nu mice (n = 93) were transplanted with human GIST xenografts with KIT exon 11+17 (UZLX-GIST9 KIT 11+17 ), exon 11 (UZLX-GIST3 KIT 11 ), or exon 9 (UZLX-GIST2B KIT9 ) mutations, respectively. In all models, avapritinib resulted in reduction of tumor volume, significant inhibition of proliferation, and reduced KIT signaling. In two models, avapritinib led to remarkable histologic responses, increase in apoptosis, and inhibition of MAPK-phosphorylation. Reference: Clin Cancer Res. 2019 Jan 15;25(2):609-618. https://clincancerres.aacrjournals.org/content/25/2/609.long

	Solvent	mg/mL	mM
Solubility
	DMSO	83.1	166.70

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 498.57 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. Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV. Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines. Mol Pharm. 2019 Jul 1;16(7):3040-3052. doi: 10.1021/acs.molpharmaceut.9b00274. Epub 2019 Jun 4. PMID: 31117741; PMCID: PMC6620786. 2. Gebreyohannes YK, Wozniak A, Zhai ME, Wellens J, Cornillie J, Vanleeuw U, Evans E, Gardino AK, Lengauer C, Debiec-Rychter M, Sciot R, Schöffski P. Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors. Clin Cancer Res. 2019 Jan 15;25(2):609-618. doi: 10.1158/1078-0432.CCR-18-1858. Epub 2018 Oct 1. PMID: 30274985.

In vitro protocol:

In vivo protocol:

1. Gebreyohannes YK, Wozniak A, Zhai ME, Wellens J, Cornillie J, Vanleeuw U, Evans E, Gardino AK, Lengauer C, Debiec-Rychter M, Sciot R, Schöffski P. Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors. Clin Cancer Res. 2019 Jan 15;25(2):609-618. doi: 10.1158/1078-0432.CCR-18-1858. Epub 2018 Oct 1. PMID: 30274985.

1: Dhillon S. Avapritinib: First Approval. Drugs. 2020 Mar;80(4):433-439. doi: 10.1007/s40265-020-01275-2. PMID: 32100250. 2: Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006–. Avapritinib. 2020 Oct 19. PMID: 33104319. 3: Kang YK, George S, Jones RL, Rutkowski P, Shen L, Mir O, Patel S, Zhou Y, von Mehren M, Hohenberger P, Villalobos V, Brahmi M, Tap WD, Trent J, Pantaleo MA, Schöffski P, He K, Hew P, Newberry K, Roche M, Heinrich MC, Bauer S. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J Clin Oncol. 2021 Oct 1;39(28):3128-3139. doi: 10.1200/JCO.21.00217. Epub 2021 Aug 3. PMID: 34343033; PMCID: PMC8478403. 4: DeAngelo DJ, Radia DH, George TI, Robinson WA, Quiery AT, Drummond MW, Bose P, Hexner EO, Winton EF, Horny HP, Tugnait M, Schmidt-Kittler O, Evans EK, Lin HM, Mar BG, Verstovsek S, Deininger MW, Gotlib J. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med. 2021 Dec;27(12):2183-2191. doi: 10.1038/s41591-021-01538-9. Epub 2021 Dec 6. PMID: 34873347; PMCID: PMC8674134. 5: Reiter A, Schwaab J, DeAngelo DJ, Gotlib J, Deininger MW, Pettit KM, Alvarez- Twose I, Vannucchi AM, Panse J, Platzbecker U, Hermine O, Dybedal I, Lin HM, Rylova SN, Ehlert K, Dimitrijević S, Radia DH. Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis. Blood Adv. 2022 Nov 8;6(21):5750-5762. doi: 10.1182/bloodadvances.2022007539. PMID: 35640224; PMCID: PMC9647833. 6: Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, Schöffski P, Cassier PA, Mir O, Chawla SP, Eskens FALM, Rutkowski P, Tap WD, Zhou T, Roche M, Bauer S. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021 Mar;145:132-142. doi: 10.1016/j.ejca.2020.12.008. Epub 2021 Jan 16. PMID: 33465704; PMCID: PMC9518931. 7: Grunewald S, Klug LR, Mühlenberg T, Lategahn J, Falkenhorst J, Town A, Ehrt C, Wardelmann E, Hartmann W, Schildhaus HU, Treckmann J, Fletcher JA, Jung S, Czodrowski P, Miller S, Schmidt-Kittler O, Rauh D, Heinrich MC, Bauer S. Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain. Cancer Discov. 2021 Jan;11(1):108-125. doi: 10.1158/2159-8290.CD-20-0487. Epub 2020 Sep 24. PMID: 32972961. 8: Below S, Michaelis LC. Avapritinib in the Treatment of Systemic Mastocytosis: an Update. Curr Hematol Malig Rep. 2021 Oct;16(5):464-472. doi: 10.1007/s11899-021-00650-4. Epub 2021 Sep 27. PMID: 34580817. 9: Alzofon N, Jimeno A. Avapritinib for metastatic or unresectable gastrointestinal stromal tumors. Drugs Today (Barc). 2020 Sep;56(9):561-571. doi: 10.1358/dot.2020.56.9.3170808. PMID: 33025950. 10: Reiter A, Gotlib J, Álvarez-Twose I, Radia DH, Lübke J, Bobbili PJ, Wang A, Norregaard C, Dimitrijevic S, Sullivan E, Louie-Gao M, Schwaab J, Galinsky IA, Perkins C, Sperr WR, Sriskandarajah P, Chin A, Sendhil SR, Duh MS, Valent P, DeAngelo DJ. Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis. Leukemia. 2022 Aug;36(8):2108-2120. doi: 10.1038/s41375-022-01615-z. Epub 2022 Jul 5. PMID: 35790816; PMCID: PMC9343245. 11: Sumbly V, Landry I, Iqbal S, Bhatti Z, Alshamam MS, Ashfaq S, Rizzo V. The Role of Avapritinib for the Treatment of Systemic Mastocytosis. Cureus. 2021 Sep 29;13(9):e18385. doi: 10.7759/cureus.18385. PMID: 34729266; PMCID: PMC8556140. 12: Dadrass F, Han J, Gaddis KJ, Swick M. Avapritinib-induced photo-aggravated cutaneous reaction. JAAD Case Rep. 2022 Jan 6;21:43-45. doi: 10.1016/j.jdcr.2021.12.019. PMID: 35146099; PMCID: PMC8818934. 13: Avapritinib (Ayvakit) for GIST. Med Lett Drugs Ther. 2021 Feb 8;63(1617):23-24. PMID: 33647006. 14: Bose P, Verstovsek S. Avapritinib for Systemic Mastocytosis. Expert Rev Hematol. 2021 Aug;14(8):687-696. doi: 10.1080/17474086.2021.1959315. Epub 2021 Aug 6. PMID: 34289787. 15: Gotlib J, Reiter A, DeAngelo DJ. Avapritinib for advanced systemic mastocytosis. Blood. 2022 Oct 13;140(15):1667-1673. doi: 10.1182/blood.2021014612. PMID: 35877999. 16: Heinrich MC, Jones RL, von Mehren M, Schöffski P, Serrano C, Kang YK, Cassier PA, Mir O, Eskens F, Tap WD, Rutkowski P, Chawla SP, Trent J, Tugnait M, Evans EK, Lauz T, Zhou T, Roche M, Wolf BB, Bauer S, George S. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020 Jul;21(7):935-946. doi: 10.1016/S1470-2045(20)30269-2. Erratum in: Lancet Oncol. 2020 Sep;21(9):e418. PMID: 32615108. 17: Gotlib J, Reiter A, Radia DH, Deininger MW, George TI, Panse J, Vannucchi AM, Platzbecker U, Alvarez-Twose I, Mital A, Hermine O, Dybedal I, Hexner EO, Hicks LK, Span L, Mesa R, Bose P, Pettit KM, Heaney ML, Oh ST, Sen J, Lin HM, Mar BG, DeAngelo DJ. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med. 2021 Dec;27(12):2192-2199. doi: 10.1038/s41591-021-01539-8. Epub 2021 Dec 6. PMID: 34873345; PMCID: PMC8674139. 18: Smrke A, Gennatas S, Huang P, Jones RL. Avapritinib in the treatment of PDGFRA exon 18 mutated gastrointestinal stromal tumors. Future Oncol. 2020 Aug;16(22):1639-1646. doi: 10.2217/fon-2020-0348. Epub 2020 Jun 10. PMID: 32517495. 19: Lee H, Li T, Wisell J, Schowinsky J, Robinson WA. Avapritinib for Cutaneous Mastocytosis. Acta Derm Venereol. 2021 Jan 5;101(1):adv00362. doi: 10.2340/00015555-3709. PMID: 33241424; PMCID: PMC9309867. 20: Pardanani A. Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management. Am J Hematol. 2021 Apr 1;96(4):508-525. doi: 10.1002/ajh.26118. Epub 2021 Feb 21. PMID: 33524167.