Dubermatinib | TP-0903 | CAS#1341200-45-0 | Tyrosine Kinase Inhibitor, Antineoplastic

MedKoo Cat#: 206462 | Name: Dubermatinib

Description:

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

Dubermatinib, also known as TP-0903, is a potent and selective AXL inhibitor. TP-0903 induces massive apoptosis in CLL B cells with LD50 values of nanomolar ranges. Combination of TP-0903 with BTK inhibitors augments CLL B-cell apoptosis AXL overexpression is a reoccurring theme observed in multiple tumor types that have acquired resistance to various agents. Treatment of cancer cells with TP-0903 reverses the mesenchymal phenotype in multiple models and sensitizes cancer cells to treatment with other targeted agents. Administration of TP-0903 either as a single agent or in combination with BTK inhibitors may be effective in treating patients with CLL.

Chemical Structure

Dubermatinib

CAS#1341200-45-0 (free base)

Theoretical Analysis

MedKoo Cat#: 206462

Name: Dubermatinib

CAS#: 1341200-45-0 (free base)

Chemical Formula: C24H30ClN7O2S

Exact Mass: 515.1870

Molecular Weight: 516.06

Elemental Analysis: C, 55.86; H, 5.86; Cl, 6.87; N, 19.00; O, 6.20; S, 6.21

Price and Availability

Size	Price	Availability
10mg	USD 90.00	Ready to ship
25mg	USD 150.00	Ready to ship
50mg	USD 250.00	Ready to ship
100mg	USD 450.00	Ready to ship
200mg	USD 750.00	Ready to ship
500mg	USD 1,550.00	Ready to ship
1g	USD 2,450.00	Ready to ship
2g	USD 3,650.00	2 Weeks

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Related CAS #

2305089-34-1 (tartrate) 1341200-45-0 (free base)

Synonym

TP-0903; TP 0903; TP0903; Dubermatinib

IUPAC/Chemical Name

2-((5-chloro-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide

InChi Key

YUAALFPUEOYPNX-UHFFFAOYSA-N

InChi Code

InChI=1S/C24H30ClN7O2S/c1-30(2)35(33,34)22-7-5-4-6-21(22)28-23-20(25)16-26-24(29-23)27-19-10-8-18(9-11-19)17-32-14-12-31(3)13-15-32/h4-11,16H,12-15,17H2,1-3H3,(H2,26,27,28,29)

SMILES Code

O=S(C1=CC=CC=C1NC2=NC(NC3=CC=C(CN4CCN(C)CC4)C=C3)=NC=C2Cl)(N(C)C)=O

Appearance

Off white to orange solid powder

Purity

>97% (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#A9T05K14

QC Data

View QC data: current batch, Lot#A9T05K14

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Dubermatinib (TP-0903) is an Axl receptor tyrosine kinase inhibitor with an IC50 value of 27 nM.

In vitro activity:

A dose-dependent induction of massive apoptosis was noted in these high-risk CLL B-cells following TP-0903 treatment (Fig. 2C). The mean LD50 doses of both the CLL cohorts (17p13.1 and 11q22.3) were comparable and very close to that obtained for the low-risk CLL B-cells (Fig. 2B). Together, these results suggest that TP-0903 could be an effective therapeutic option across all the CLL risk groups whose leukemic B-cells express constitutively phosphorylated Axl RTK. Reference: Clin Cancer Res. 2015 May 1; 21(9): 2115–2126. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479154/

In vivo activity:

This study used a selective and effective AXL receptor inhibitor TP0903 to assess whether AXL mediated CCD-induced neuropathic pain. This study observed the effect of repeated TP0903 (0.05, 0.50, or 1.00 μg) on CCD induced the changes in paw-withdrawal responses to mechanical, thermal, and cold stimuli on days 4 and 6 post-CCD. TP0903 or vehicle solution was intrathecally administered 1 h before CCD or sham surgery and once daily for five days after CCD or sham surgery. On days 4 and 6, ipsilateral PWTs to mechanical stimuli, PWLs to thermal stimuli, and response latencies to cold stimuli in the CCD plus vehicle group were decreased significantly compared to the sham-operation plus vehicle group (Figure 4(a)). Repeated injections of 0.50 and 1.00 μg TP0903 reversed these decreases in latency (Figure 4(a) to (c)). Also on days 4 and 6 after CCD surgery, PWTs to mechanical, PWLs to thermal, and positive response latencies to cold stimulation were much higher on the ipsilateral side of the TP0903 plus CCD group than in the CCD plus vehicle group (Figure 4(a): F(15,191) = 10.38, Figure 4(b): F(15,191) = 7.33, Figure 4(c): F(15,191) = 16.96, **P < 0.01, vs. Sham + Veh, ##P < 0.01, vs. CCD + Veh). Reference: Mol Pain. 2020; 16: 1744806919900814. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970473/

	Solvent	mg/mL	mM
Solubility
	DMSO	3.2	6.14
	Ethanol	2.0	3.88

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 516.06 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. Jeon JY, Buelow DR, Garrison DA, Niu M, Eisenmann ED, Huang KM, Zavorka Thomas ME, Weber RH, Whatcott CJ, Warner SL, Orwick SJ, Carmichael B, Stahl E, Brinton LT, Lapalombella R, Blachly JS, Hertlein E, Byrd JC, Bhatnagar B, Baker SD. TP-0903 is active in models of drug-resistant acute myeloid leukemia. JCI Insight. 2020 Dec 3;5(23):e140169. doi: 10.1172/jci.insight.140169. PMID: 33268594; PMCID: PMC7714403. 2. Sinha S, Boysen J, Nelson M, Secreto C, Warner SL, Bearss DJ, Lesnick C, Shanafelt TD, Kay NE, Ghosh AK. Targeted Axl Inhibition Primes Chronic Lymphocytic Leukemia B Cells to Apoptosis and Shows Synergistic/Additive Effects in Combination with BTK Inhibitors. Clin Cancer Res. 2015 May 1;21(9):2115-26. doi: 10.1158/1078-0432.CCR-14-1892. Epub 2015 Feb 11. PMID: 25673699; PMCID: PMC4479154. 3. Taverna JA, Hung CN, DeArmond DT, Chen M, Lin CL, Osmulski PA, Gaczynska ME, Wang CM, Lucio ND, Chou CW, Chen CL, Nazarullah A, Lampkin SR, Qiu L, Bearss DJ, Warner S, Whatcott CJ, Mouritsen L, Wade M, Weitman S, Mesa RA, Kirma NB, Chao WT, Huang TH. Single-Cell Proteomic Profiling Identifies Combined AXL and JAK1 Inhibition as a Novel Therapeutic Strategy for Lung Cancer. Cancer Res. 2020 Apr 1;80(7):1551-1563. doi: 10.1158/0008-5472.CAN-19-3183. Epub 2020 Jan 28. PMID: 31992541; PMCID: PMC7127959. 4. Liang L, Zhang J, Tian L, Wang S, Xu L, Wang Y, Guo-Shuai Q, Dong Y, Chen Y, Jia H, Yang X, Yuan C. AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats. Mol Pain. 2020 Jan-Dec;16:1744806919900814. doi: 10.1177/1744806919900814. PMID: 31884887; PMCID: PMC6970473.

In vitro protocol:

In vivo protocol:

1. Taverna JA, Hung CN, DeArmond DT, Chen M, Lin CL, Osmulski PA, Gaczynska ME, Wang CM, Lucio ND, Chou CW, Chen CL, Nazarullah A, Lampkin SR, Qiu L, Bearss DJ, Warner S, Whatcott CJ, Mouritsen L, Wade M, Weitman S, Mesa RA, Kirma NB, Chao WT, Huang TH. Single-Cell Proteomic Profiling Identifies Combined AXL and JAK1 Inhibition as a Novel Therapeutic Strategy for Lung Cancer. Cancer Res. 2020 Apr 1;80(7):1551-1563. doi: 10.1158/0008-5472.CAN-19-3183. Epub 2020 Jan 28. PMID: 31992541; PMCID: PMC7127959. 2. Liang L, Zhang J, Tian L, Wang S, Xu L, Wang Y, Guo-Shuai Q, Dong Y, Chen Y, Jia H, Yang X, Yuan C. AXL signaling in primary sensory neurons contributes to chronic compression of dorsal root ganglion-induced neuropathic pain in rats. Mol Pain. 2020 Jan-Dec;16:1744806919900814. doi: 10.1177/1744806919900814. PMID: 31884887; PMCID: PMC6970473.

1: Taverna JA, Hung CN, DeArmond DT, Chen M, Lin CL, Osmulski PA, Gaczynska ME, Wang CM, Lucio ND, Chou CW, Chen CL, Nazarullah A, Lampkin SR, Qiu L, Bearss DJ, Warner S, Whatcott CJ, Mouritsen L, Wade M, Weitman S, Mesa RA, Kirma NB, Chao WT, Huang TH. Single-Cell Proteomic Profiling Identifies Combined AXL and JAK1 Inhibition as a Novel Therapeutic Strategy for Lung Cancer. Cancer Res. 2020 Apr 1;80(7):1551-1563. doi: 10.1158/0008-5472.CAN-19-3183. Epub 2020 Jan 28. PMID: 31992541; PMCID: PMC7127959. 2: Zhang Y, Arner EN, Rizvi A, Toombs JE, Huang H, Warner SL, Foulks JM, Brekken RA. AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer. Mol Cancer Ther. 2022 Jan;21(1):38-47. doi: 10.1158/1535-7163.MCT-21-0293. Epub 2021 Oct 21. PMID: 34675118; PMCID: PMC8742768. 3: Kim SH, Choi S, Lee WS. Bevacizumab and anexelekto inhibitor, TP-0903 inhibits TGF-β1-induced epithelial-mesenchymal transition of colon cancer cells. Anticancer Drugs. 2022 Jan 1;33(1):e453-e461. doi: 10.1097/CAD.0000000000001239. PMID: 34538864. 4: Jeon JY, Buelow DR, Garrison DA, Niu M, Eisenmann ED, Huang KM, Zavorka Thomas ME, Weber RH, Whatcott CJ, Warner SL, Orwick SJ, Carmichael B, Stahl E, Brinton LT, Lapalombella R, Blachly JS, Hertlein E, Byrd JC, Bhatnagar B, Baker SD. TP-0903 is active in models of drug-resistant acute myeloid leukemia. JCI Insight. 2020 Dec 3;5(23):e140169. doi: 10.1172/jci.insight.140169. PMID: 33268594; PMCID: PMC7714403. 5: Hung CN, Chen M, DeArmond DT, Chiu CH, Limboy CA, Tan X, Kusi M, Chou CW, Lin LL, Zhang Z, Wang CM, Chen CL, Mitsuya K, Osmulski PA, Gaczynska ME, Kirma NB, Vadlamudi RK, Gibbons DL, Warner S, Brenner AJ, Mahadevan D, Michalek JE, Huang TH, Taverna JA. AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages. Cell Rep. 2023 Sep 26;42(9):113067. doi: 10.1016/j.celrep.2023.113067. Epub 2023 Sep 1. PMID: 37659081. 6: Aveic S, Corallo D, Porcù E, Pantile M, Boso D, Zanon C, Viola G, Sidarovich V, Mariotto E, Quattrone A, Basso G, Tonini GP. TP-0903 inhibits neuroblastoma cell growth and enhances the sensitivity to conventional chemotherapy. Eur J Pharmacol. 2018 Jan 5;818:435-448. doi: 10.1016/j.ejphar.2017.11.016. Epub 2017 Nov 14. PMID: 29154838. 7: Patel V, Keating MJ, Wierda WG, Gandhi V. Preclinical combination of TP-0903, an AXL inhibitor and B-PAC-1, a procaspase-activating compound with ibrutinib in chronic lymphocytic leukemia. Leuk Lymphoma. 2016;57(6):1494-7. doi: 10.3109/10428194.2015.1102243. Epub 2015 Nov 16. PMID: 26440741; PMCID: PMC4963009. 8: Wei S, Chang S, Dong Y, Xu L, Yuan X, Jia H, Zhang J, Liang L. Electro- acupuncture Suppresses AXL Expression in Dorsal Root Ganglion Neurons and Enhances Analgesic Effect of AXL Inhibitor in Spinal Nerve Ligation Induced- Neuropathic Pain Rats. Neurochem Res. 2021 Mar;46(3):504-512. doi: 10.1007/s11064-020-03185-x. Epub 2021 Jan 2. PMID: 33387191. 9: Jimenez L, Wang J, Morrison MA, Whatcott C, Soh KK, Warner S, Bearss D, Jette CA, Stewart RA. Phenotypic chemical screening using a zebrafish neural crest EMT reporter identifies retinoic acid as an inhibitor of epithelial morphogenesis. Dis Model Mech. 2016 Apr;9(4):389-400. doi: 10.1242/dmm.021790. Epub 2016 Jan 21. PMID: 26794130; PMCID: PMC4852498. 10: Sinha S, Boysen J, Nelson M, Secreto C, Warner SL, Bearss DJ, Lesnick C, Shanafelt TD, Kay NE, Ghosh AK. Targeted Axl Inhibition Primes Chronic Lymphocytic Leukemia B Cells to Apoptosis and Shows Synergistic/Additive Effects in Combination with BTK Inhibitors. Clin Cancer Res. 2015 May 1;21(9):2115-26. doi: 10.1158/1078-0432.CCR-14-1892. Epub 2015 Feb 11. PMID: 25673699; PMCID: PMC4479154.