Avapritinib
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Hodoodo CAT#: H206816

CAS#: 1703793-34-3

Description: 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

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Avapritinib
CAS# 1703793-34-3

Theoretical Analysis

Hodoodo Cat#: H206816
Name: Avapritinib
CAS#: 1703793-34-3
Chemical Formula: C26H27FN10
Exact Mass: 498.24
Molecular Weight: 498.570
Elemental Analysis: C, 62.64; H, 5.46; F, 3.81; N, 28.09

Price and Availability

Size Price Availability Quantity
5mg USD 85 Ready to ship
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1250 Ready to Ship
500mg USD 2850 Ready to Ship
1g USD 4250 Ready to Ship
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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:

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

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 83.1 166.70

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.

Recalculate based on batch purity %
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: 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.
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.

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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.


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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.


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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.


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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.