Altiratinib
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MedKoo CAT#: 206143

CAS#: 1345847-93-9

Description: Altiratinib, also known as DCC-270, DP-5164, is an oral, selective and highly potent inhibitor of MET, TIE2, VEGFR2 and TRK kinases with potential anticancer activity. DCC-2701 effectively reduces tumor burden in vivo and blocks c-MET pTyr(1349)-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro. Importantly, DCC-2701's anti-proliferative activity was dependent on c-MET activation induced by stromal human fibroblasts and to a lesser extent exogenous HGF.

Chemical Structure

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Altiratinib
CAS# 1345847-93-9
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206143
Name: Altiratinib
CAS#: 1345847-93-9
Chemical Formula: C26H21F3N4O4
Exact Mass: 510.15
Molecular Weight: 510.460
Elemental Analysis: C, 61.18; H, 4.15; F, 11.17; N, 10.98; O, 12.54

Price and Availability

Size Price Availability Quantity
10mg USD 90 Ready to ship
25mg USD 150 Ready to ship
50mg USD 250 Ready to ship
100mg USD 450 Ready to ship
200mg USD 750 Ready to ship
500mg USD 1650 Ready to ship
1g USD 2950 Ready to ship
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Synonym: DCC2701; DCC 2701; DCC-2701; DP 5164; DP5164; DP-5164; Altiratinib.

IUPAC/Chemical Name: N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

InChi Key: GNNDEPIMDAZHRQ-UHFFFAOYSA-N

InChi Code: InChI=1S/C26H21F3N4O4/c27-15-3-5-16(6-4-15)31-24(35)26(8-9-26)25(36)32-20-12-19(29)21(13-18(20)28)37-17-7-10-30-22(11-17)33-23(34)14-1-2-14/h3-7,10-14H,1-2,8-9H2,(H,31,35)(H,32,36)(H,30,33,34)

SMILES Code: O=C(C1(C(NC2=CC=C(F)C=C2)=O)CC1)NC3=CC(F)=C(OC4=CC(NC(C5CC5)=O)=NC=C4)C=C3F

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:         

Biological target: Altiratinib (DCC-2701) is a multi-targeted kinase inhibitor with IC50s of 2.7, 8, 9.2, 9.3, 0.85, 4.6, 0.83 nM for MET, TIE2, VEGFR2, FLT3, Trk1, Trk2, and Trk3 respectively.
In vitro activity: Here this study tested if the type II inhibitor altiratinib would suppress the growth of Ba/F3 TPM3-NTRK1G595R and ETV6-NTRK3G623R cells using viability assays. These data show that NTRK1G595R is resistant to both larotrectinib and altiratinib (Fig. 2a, b). However, NTRK3G623R retains partial sensitivity to altiratinib (IC50 ~ 240 nM) as compared to near-total resistance to larotrectinib (IC50 > 2000 nM). This study performed immunoblotting to assess on-target NTRK inhibition from treated Ba/F3 cell lysates. These data suggest that altiratinib may indeed retain some inhibitory propensity against NTRK3G623R as compared to NTRK1G595R (Fig. 2c, d). Densitometry reveals that NTRKG623R autophosphorylation is ~95% attenuated with 250 nM altiratinib (Fig. 2d, Supplementary Fig. 3b) whereas 250 nM larotrectinib inhibited NTRKG623R by only ~41% (Fig. 2d, Supplementary Fig. 3a). Reference: Commun Biol. 2020; 3: 776. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745027/
In vivo activity: Altiratinib was evaluated in the MET-amplified MKN-45 xenograft mouse model to determine the pharmacokinetic/pharmacodynamic relationship for in vivo MET target inhibition. A single oral dose of 30 mg/kg altiratinib led to >95% inhibition of MET phosphorylation for the entire 24-hour period (Supplementary Table S4A). A single 10 mg/kg oral dose of altiratinib (Fig. 2D; Supplementary Table S4B) exhibited complete inhibition of MET phosphorylation through 12 hours and 73% inhibition at 24 hours postdose [factoring in plasma protein binding (98.7% bound)], the free drug concentrations required for MET inhibition correlated with in vitro results (IC50 ≈ 1.1 ng/mL = 2.2 nmol/L; Table 2). Reference: Mol Cancer Ther. 2015 Sep;14(9):2023-34. https://mct.aacrjournals.org/content/14/9/2023.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 10.0 19.59

Preparing Stock Solutions

The following data is based on the product molecular weight 510.46 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. Somwar R, Hofmann NE, Smith B, Odintsov I, Vojnic M, Linkov I, Tam A, Khodos I, Mattar MS, de Stanchina E, Flynn D, Ladanyi M, Drilon A, Shinde U, Davare MA. NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors. Commun Biol. 2020 Dec 16;3(1):776. doi: 10.1038/s42003-020-01508-w. PMID: 33328556; PMCID: PMC7745027. 2. Kwon Y, Smith BD, Zhou Y, Kaufman MD, Godwin AK. Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment. Oncogene. 2015 Jan 8;34(2):144-53. doi: 10.1038/onc.2013.539. Epub 2013 Dec 23. PMID: 24362531; PMCID: PMC4067476. 3. Piao Y, Park SY, Henry V, Smith BD, Tiao N, Flynn DL, de Groot JF. Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models. Neuro Oncol. 2016 Sep;18(9):1230-41. doi: 10.1093/neuonc/now030. Epub 2016 Mar 9. PMID: 26965451; PMCID: PMC4998992. 4. Smith BD, Kaufman MD, Leary CB, Turner BA, Wise SC, Ahn YM, Booth RJ, Caldwell TM, Ensinger CL, Hood MM, Lu WP, Patt TW, Patt WC, Rutkoski TJ, Samarakoon T, Telikepalli H, Vogeti L, Vogeti S, Yates KM, Chun L, Stewart LJ, Clare M, Flynn DL. Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2. Mol Cancer Ther. 2015 Sep;14(9):2023-34. doi: 10.1158/1535-7163.MCT-14-1105. Epub 2015 Aug 18. PMID: 26285778.
In vitro protocol: 1. Somwar R, Hofmann NE, Smith B, Odintsov I, Vojnic M, Linkov I, Tam A, Khodos I, Mattar MS, de Stanchina E, Flynn D, Ladanyi M, Drilon A, Shinde U, Davare MA. NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors. Commun Biol. 2020 Dec 16;3(1):776. doi: 10.1038/s42003-020-01508-w. PMID: 33328556; PMCID: PMC7745027. 2. Kwon Y, Smith BD, Zhou Y, Kaufman MD, Godwin AK. Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment. Oncogene. 2015 Jan 8;34(2):144-53. doi: 10.1038/onc.2013.539. Epub 2013 Dec 23. PMID: 24362531; PMCID: PMC4067476.
In vivo protocol: 1. Piao Y, Park SY, Henry V, Smith BD, Tiao N, Flynn DL, de Groot JF. Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models. Neuro Oncol. 2016 Sep;18(9):1230-41. doi: 10.1093/neuonc/now030. Epub 2016 Mar 9. PMID: 26965451; PMCID: PMC4998992. 2. Smith BD, Kaufman MD, Leary CB, Turner BA, Wise SC, Ahn YM, Booth RJ, Caldwell TM, Ensinger CL, Hood MM, Lu WP, Patt TW, Patt WC, Rutkoski TJ, Samarakoon T, Telikepalli H, Vogeti L, Vogeti S, Yates KM, Chun L, Stewart LJ, Clare M, Flynn DL. Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2. Mol Cancer Ther. 2015 Sep;14(9):2023-34. doi: 10.1158/1535-7163.MCT-14-1105. Epub 2015 Aug 18. PMID: 26285778.

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1: Swale C, Bellini V, Bowler MW, Flore N, Brenier-Pinchart MP, Cannella D, Belmudes L, Mas C, Couté Y, Laurent F, Scherf A, Bougdour A, Hakimi MA. Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a spliceosome kinase. Sci Transl Med. 2022 Aug 3;14(656):eabn3231. doi: 10.1126/scitranslmed.abn3231. Epub 2022 Aug 3. PMID: 35921477.


2: Fujino T, Suda K, Koga T, Hamada A, Ohara S, Chiba M, Shimoji M, Takemoto T, Soh J, Mitsudomi T. Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation. J Hematol Oncol. 2022 Jun 11;15(1):79. doi: 10.1186/s13045-022-01299-z. PMID: 35690785; PMCID: PMC9188708.


3: Smith BD, Kaufman MD, Leary CB, Turner BA, Wise SC, Ahn YM, Booth RJ, Caldwell TM, Ensinger CL, Hood MM, Lu WP, Patt TW, Patt WC, Rutkoski TJ, Samarakoon T, Telikepalli H, Vogeti L, Vogeti S, Yates KM, Chun L, Stewart LJ, Clare M, Flynn DL. Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2. Mol Cancer Ther. 2015 Sep;14(9):2023-34. doi: 10.1158/1535-7163.MCT-14-1105. Epub 2015 Aug 18. PMID: 26285778.


4: Piao Y, Park SY, Henry V, Smith BD, Tiao N, Flynn DL, de Groot JF. Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models. Neuro Oncol. 2016 Sep;18(9):1230-41. doi: 10.1093/neuonc/now030. Epub 2016 Mar 9. PMID: 26965451; PMCID: PMC4998992.


5: Somwar R, Hofmann NE, Smith B, Odintsov I, Vojnic M, Linkov I, Tam A, Khodos I, Mattar MS, de Stanchina E, Flynn D, Ladanyi M, Drilon A, Shinde U, Davare MA. NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors. Commun Biol. 2020 Dec 16;3(1):776. doi: 10.1038/s42003-020-01508-w. PMID: 33328556; PMCID: PMC7745027.


6: Olmez I, Zhang Y, Manigat L, Benamar M, Brenneman B, Nakano I, Godlewski J, Bronisz A, Lee J, Abbas T, Abounader R, Purow B. Combined c-Met/Trk Inhibition Overcomes Resistance to CDK4/6 Inhibitors in Glioblastoma. Cancer Res. 2018 Aug 1;78(15):4360-4369. doi: 10.1158/0008-5472.CAN-17-3124. Epub 2018 May 29. PMID: 29844123; PMCID: PMC6072607.


7: Yoo H, Lee HR, Kim KH, Kim MA, Bang S, Kang YH, Kim WH, Song Y, Chang SE. CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders. Theranostics. 2021 Oct 17;11(20):9918-9936. doi: 10.7150/thno.66378. PMID: 34815795; PMCID: PMC8581419.