Entospletinib
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MedKoo CAT#: 206107

CAS#: 1229208-44-9 (free base)

Description: Entospletinib, also known as GS-9973, is a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications. In Phase II clinical trials, Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity.

Chemical Structure

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Entospletinib
CAS# 1229208-44-9 (free base)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206107
Name: Entospletinib
CAS#: 1229208-44-9 (free base)
Chemical Formula: C23H21N7O
Exact Mass: 411.18
Molecular Weight: 411.460
Elemental Analysis: C, 67.14; H, 5.14; N, 23.83; O, 3.89

Price and Availability

Size Price Availability Quantity
10mg USD 125 Ready to ship
25mg USD 250 Ready to ship
50mg USD 425 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1250 Ready to ship
500mg USD 2850 Ready to ship
1g USD 3950 Ready to ship
2g USD 6550 Ready to ship
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Related CAS #: 1648797-46-9 (dimesylate)   1229208-44-9 (free base)  

Synonym: Entospletinib; GS9973; GS 9973; GS-9973.

IUPAC/Chemical Name: 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine

InChi Key: XSMSNFMDVXXHGJ-UHFFFAOYSA-N

InChi Code: InChI=1S/C23H21N7O/c1-2-17-14-25-28-20(17)13-16(1)21-15-30-8-7-24-23(30)22(27-21)26-18-3-5-19(6-4-18)29-9-11-31-12-10-29/h1-8,13-15H,9-12H2,(H,25,28)(H,26,27)

SMILES Code: C12=NC=CN1C=C(C3=CC4=C(C=C3)C=NN4)N=C2NC5=CC=C(N6CCOCC6)C=C5

Appearance: 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, 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: Entospletinib (GS-9973) is a Syk inhibitor with an IC50 of 7.7 nM.
In vitro activity: The effects of a Btk inhibitor, tirabrutinib, and a Syk inhibitor, entospletinib, were investigated alone and in combination on platelet signaling and functions in vitro. Entospletinib alone efficiently inhibited washed platelet aggregation in response to collagen. However, entospletinib only weakly affected platelet activation in platelet-rich plasma. Importantly, the combination of tirabrutinib and entospletinib induced a significant decrease in platelet response to collagen in vitro. Reference: J Thromb Haemost. 2020 Dec;18(12):3336-3351. https://onlinelibrary.wiley.com/doi/10.1111/jth.15098
In vivo activity: Potential utility of ENTO (Entospletinib) as GVHD (graft-versus-host disease) prophylaxis was examined using a preclinical mouse model of eye and skin GVHD and ENTO-compounded chow. Early SYK inhibition improved blood immune cell reconstitution in GVHD mice and prolonged survival, with 60% of mice surviving to day +120 compared with 10% of mice treated with placebo. Compared with mice receiving placebo, mice receiving ENTO had dramatic improvements in clinical eye scores, alopecia scores, and skin scores. Reference: JCI Insight. 2018 Oct 4;3(19):e122430. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237454/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 34.5 83.85
DMSO:PBS (pH 7.2) (1:2) 0.3 0.73

Preparing Stock Solutions

The following data is based on the product molecular weight 411.46 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. Series J, Ribes A, Garcia C, Souleyreau P, Bauters A, Morschhauser F, Jürgensmeier JM, Sié P, Ysebaert L, Payrastre B. Effects of novel Btk and Syk inhibitors on platelet functions alone and in combination in vitro and in vivo. J Thromb Haemost. 2020 Dec;18(12):3336-3351. doi: 10.1111/jth.15098. Epub 2020 Oct 26. PMID: 32926549. 2. Poe JC, Jia W, Di Paolo JA, Reyes NJ, Kim JY, Su H, Sundy JS, Cardones AR, Perez VL, Chen BJ, Chao NJ, Cardona DM, Saban DR, Sarantopoulos S. SYK inhibitor entospletinib prevents ocular and skin GVHD in mice. JCI Insight. 2018 Oct 4;3(19):e122430. doi: 10.1172/jci.insight.122430. PMID: 30282825; PMCID: PMC6237454.
In vitro protocol: 1. Series J, Ribes A, Garcia C, Souleyreau P, Bauters A, Morschhauser F, Jürgensmeier JM, Sié P, Ysebaert L, Payrastre B. Effects of novel Btk and Syk inhibitors on platelet functions alone and in combination in vitro and in vivo. J Thromb Haemost. 2020 Dec;18(12):3336-3351. doi: 10.1111/jth.15098. Epub 2020 Oct 26. PMID: 32926549.
In vivo protocol: 1. Poe JC, Jia W, Di Paolo JA, Reyes NJ, Kim JY, Su H, Sundy JS, Cardones AR, Perez VL, Chen BJ, Chao NJ, Cardona DM, Saban DR, Sarantopoulos S. SYK inhibitor entospletinib prevents ocular and skin GVHD in mice. JCI Insight. 2018 Oct 4;3(19):e122430. doi: 10.1172/jci.insight.122430. PMID: 30282825; PMCID: PMC6237454.

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1: Walker AR, Byrd JC, Blachly JS, Bhatnagar B, Mims AS, Orwick S, Lin TL, Crosswell HE, Zhang D, Minden MD, Munugalavadla V, Long L, Liu J, Pan Y, Oellerich T, Serve H, Rao AV, Blum WG. Entospletinib in Combination with Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of HOXA9 and MEIS1 Expression. Clin Cancer Res. 2020 Nov 15;26(22):5852-5859. doi: 10.1158/1078-0432.CCR-20-1064. Epub 2020 Aug 20. PMID: 32820015.


2: Kittai AS, Best S, Thurlow B, Lam V, Hashiguchi T, Goodyear S, Persky DO, Okada C, Park B, Spurgeon SE, Danilov AV. Entospletinib and obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia and B-cell malignancies. Haematologica. 2021 Jul 1;106(7):2022-2025. doi: 10.3324/haematol.2020.270298. PMID: 33504141; PMCID: PMC8252925.


3: Loftus JP, Yahiaoui A, Brown PA, Niswander LM, Bagashev A, Wang M, Schauf A, Tannheimer S, Tasian SK. Combinatorial efficacy of entospletinib and chemotherapy in patient-derived xenograft models of infant acute lymphoblastic leukemia. Haematologica. 2021 Apr 1;106(4):1067-1078. doi: 10.3324/haematol.2019.241729. PMID: 32414848; PMCID: PMC8018117.


4: Sharman J, Di Paolo J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther Adv Hematol. 2016 Jun;7(3):157-70. doi: 10.1177/2040620716636542. Epub 2016 Mar 17. PMID: 27247756; PMCID: PMC4872176.


5: Duong VH, Ruppert AS, Mims AS, Borate U, Stein EM, Baer MR, Stock W, Kovacsovics T, Blum W, Arellano ML, Schiller GJ, Olin RL, Foran JM, Litzow MR, Lin TL, Patel PA, Foster MC, Redner RL, Al-Mansour Z, Cogle CR, Swords RT, Collins RH, Vergilio JA, Heerema NA, Rosenberg L, Yocum AO, Marcus S, Chen T, Druggan F, Stefanos M, Gana TJ, Shoben AB, Druker BJ, Burd A, Byrd JC, Levine RL, Boyiadzis MM. Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial. Cancer. 2023 Aug 1;129(15):2308-2320. doi: 10.1002/cncr.34780. Epub 2023 Apr 20. PMID: 37078412.


6: Qu C, Zheng D, Li S, Liu Y, Lidofsky A, Holmes JA, Chen J, He L, Wei L, Liao Y, Yuan H, Jin Q, Lin Z, Hu Q, Jiang Y, Tu M, Chen X, Li W, Lin W, Fuchs BC, Chung RT, Hong J. Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis. Hepatology. 2018 Sep;68(3):1125-1139. doi: 10.1002/hep.29881. Epub 2018 May 21. PMID: 29537660; PMCID: PMC6138581.


7: Tang S, Yu Q, Ding C. Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases. Expert Opin Investig Drugs. 2022 Mar;31(3):291-303. doi: 10.1080/13543784.2022.2040014. Epub 2022 Feb 18. PMID: 35130124.


8: Poe JC, Jia W, Di Paolo JA, Reyes NJ, Kim JY, Su H, Sundy JS, Cardones AR, Perez VL, Chen BJ, Chao NJ, Cardona DM, Saban DR, Sarantopoulos S. SYK inhibitor entospletinib prevents ocular and skin GVHD in mice. JCI Insight. 2018 Oct 4;3(19):e122430. doi: 10.1172/jci.insight.122430. PMID: 30282825; PMCID: PMC6237454.


9: Awan FT, Thirman MJ, Patel-Donnelly D, Assouline S, Rao AV, Ye W, Hill B, Sharman JP. Entospletinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia previously treated with B-cell receptor inhibitors: results of a phase 2 study. Leuk Lymphoma. 2019 Aug;60(8):1972-1977. doi: 10.1080/10428194.2018.1562180. Epub 2019 Jan 11. PMID: 30633573.


10: Cooper N, Ghanima W, Hill QA, Nicolson PL, Markovtsov V, Kessler C. Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib. Platelets. 2023 Dec;34(1):2131751. doi: 10.1080/09537104.2022.2131751. Epub 2022 Nov 4. PMID: 36331249.


11: Lam V, Best S, Kittai A, Orand K, Spurgeon SE, Liu T, Danilov AV. Proapoptotic and immunomodulatory effects of SYK inhibitor entospletinib in combination with obinutuzumab in patients with chronic lymphocytic leukaemia. Br J Clin Pharmacol. 2022 Feb;88(2):836-841. doi: 10.1111/bcp.14962. Epub 2021 Jul 19. PMID: 34196037.


12: Jorda R, Krajčovičová S, Králová P, Soural M, Kryštof V. Scaffold hopping of the SYK inhibitor entospletinib leads to broader targeting of the BCR signalosome. Eur J Med Chem. 2020 Oct 15;204:112636. doi: 10.1016/j.ejmech.2020.112636. Epub 2020 Jul 19. PMID: 32731189.


13: Ramanathan S, Di Paolo JA, Jin F, Shao L, Sharma S, Robeson M, Kearney BP. Pharmacokinetics, Pharmacodynamics, and Safety of Entospletinib, a Novel pSYK Inhibitor, Following Single and Multiple Oral Dosing in Healthy Volunteers. Clin Drug Investig. 2017 Feb;37(2):195-205. doi: 10.1007/s40261-016-0476-x. PMID: 27785737; PMCID: PMC5250654.


14: Andorsky DJ, Kolibaba KS, Assouline S, Forero-Torres A, Jones V, Klein LM, Patel-Donnelly D, Smith M, Ye W, Shi W, Yasenchak CA, Sharman JP. An open-label phase 2 trial of entospletinib in indolent non-Hodgkin lymphoma and mantle cell lymphoma. Br J Haematol. 2019 Jan;184(2):215-222. doi: 10.1111/bjh.15552. Epub 2018 Sep 5. PMID: 30183069; PMCID: PMC6585960.


15: Kutsch N, Pallasch C, Tausch E, Böhme V, Ritgen M, Liersch R, Wacker A, Jacobs G, Trappe RU, Dreger P, Fischer K, Fink AM, Stilgenbauer S, Zhai S, Li B, Jürgensmeier JM, Rajakumaraswamy N, Bhargava P, Hallek M, Eichhorst BF. Efficacy and Safety of the Combination of Tirabrutinib and Entospletinib With or Without Obinutuzumab in Relapsed Chronic Lymphocytic Leukemia. Hemasphere. 2022 Mar 8;6(4):e692. doi: 10.1097/HS9.0000000000000692. PMID: 35284802; PMCID: PMC8906452.


16: Narayanan S, Wu ZX, Wang JQ, Ma H, Acharekar N, Koya J, Yoganathan S, Fang S, Chen ZS, Pan Y. The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance. Int J Biol Sci. 2021 Jun 22;17(10):2652-2665. doi: 10.7150/ijbs.61229. PMID: 34326700; PMCID: PMC8315011.


17: Kong W, Sender S, Perez SV, Sekora A, Ruetgen B, Junghanss C, Nolte I, Murua Escobar H. Pan- and Isoform-specific Inhibition of the Bromodomain and Extra- terminal Proteins and Evaluation of Synergistic Potential With Entospletinib in Canine Lymphoma. Anticancer Res. 2020 Jul;40(7):3781-3792. doi: 10.21873/anticanres.14367. PMID: 32620617.


18: Burke JM, Shustov A, Essell J, Patel-Donnelly D, Yang J, Chen R, Ye W, Shi W, Assouline S, Sharman J. An Open-label, Phase II Trial of Entospletinib (GS-9973), a Selective Spleen Tyrosine Kinase Inhibitor, in Diffuse Large B-cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331. doi: 10.1016/j.clml.2018.05.022. Epub 2018 Jun 6. PMID: 29934062; PMCID: PMC6857170.


19: Sender S, Sekora A, Villa Perez S, Chabanovska O, Becker A, Ngezahayo A, Junghanss C, Murua Escobar H. Precursor B-ALL Cell Lines Differentially Respond to SYK Inhibition by Entospletinib. Int J Mol Sci. 2021 Jan 8;22(2):592. doi: 10.3390/ijms22020592. PMID: 33435587; PMCID: PMC7827334.


20: Yoshimoto T, Hayashi T, Kondo T, Kittaka M, Reichenberger EJ, Ueki Y. Second-Generation SYK Inhibitor Entospletinib Ameliorates Fully Established Inflammation and Bone Destruction in the Cherubism Mouse Model. J Bone Miner Res. 2018 Aug;33(8):1513-1519. doi: 10.1002/jbmr.3449. Epub 2018 May 22. PMID: 29669173; PMCID: PMC6351076.