Olverembatinib (GZD824)
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MedKoo CAT#: 407111

CAS#: 1257628-77-5 (free base)

Description: Olverembatinib, also known as GZD824, is a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. GZD824 tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K(d) values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC(50) values. GZD824 potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC(50) values of 0.2 and 0.13 nM, respectively. GZD824 also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I).

Chemical Structure

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Olverembatinib (GZD824)
CAS# 1257628-77-5 (free base)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 407111
Name: Olverembatinib (GZD824)
CAS#: 1257628-77-5 (free base)
Chemical Formula: C29H27F3N6O
Exact Mass: 532.22
Molecular Weight: 532.220
Elemental Analysis: C, 65.40; H, 5.11; F, 10.70; N, 15.78; O, 3.00

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 850 Ready to ship
500mg USD 1850 Ready to ship
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Related CAS #: 1257628-77-5 (free base)   1421783-64-3 (dimesylate)    

Synonym: GZD824; GZD 824; GZD-824; Olverembatinib;

IUPAC/Chemical Name: 3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

InChi Key: TZKBVRDEOITLRB-UHFFFAOYSA-N

InChi Code: InChI=1S/C29H27F3N6O/c1-19-3-5-22(14-21(19)6-4-20-13-24-17-34-36-27(24)33-16-20)28(39)35-25-8-7-23(26(15-25)29(30,31)32)18-38-11-9-37(2)10-12-38/h3,5,7-8,13-17H,9-12,18H2,1-2H3,(H,35,39)(H,33,34,36)

SMILES Code: CC1=CC=C(C=C1C#CC2=CN=C3C(C=NN3)=C2)C(NC4=CC=C(C(C(F)(F)F)=C4)CN5CCN(CC5)C)=O

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, 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: Olverembatinib (GZD824, HQP1351) is a potent and orally active pan-Bcr-Abl inhibitor that strongly inhibits native Bcr-Abl and Bcr-AblT315I with IC50s of 0.34 nM and 0.68 nM, respectively.
In vitro activity: To validate the anti-proliferation effect of GZD824 in leukemia cells, different single-gene-driven proliferation cells were selected including MV4–11Flt3-ITD, MOLM-13Flt3-ITD, KG-1 FGFR1OP2-FGFR1 and EOL-1FIP1L1-PDGFRa as models. It was shown that GZD824 inhibits the viability of all 4 cell lines with IC50 values of 2.00 ± 1.10, 6.01 ± 6.10, 3.66 ± 1.93 and 7.56 ± 2.73 nM, respectively, but was more than 50-fold less potent against other leukemia cells such as NB4 and HL60, independent of FLT3-ITD, FGFR1OP2-FGFR1 or FIP1L1-PDGFRa mutations (Table 1). The anti-proliferation activities of GZD824 were also investigated in Ba/F3 stable cells, and used three marketed FLT3 inhibitors, midostaurin, gilteritinib and quizartinib as controls. It was shown that these three FLT3 inhibitors were insensitive to FLT3-ITD-F691I and FLT3-ITD-F691R mutants, but GZD824 clearly inhibited cell growth with IC50 values of 1.4 and 9.4 nM, respectively (Table 2). GZD824 was also found to be sensitive to most cells harboring different FLT3 kinase domain mutants such as D835N//G/A and D842H/R but less sensitive to D835H/V/Y/I. Even for R834Q mutation, which is resistant to all marketed second generation FLT3 inhibitors, GZD824 possesses inhibitory activity with an IC50 value of 76.2 nM. Western blotting (WB) results showed that GZD824 clearly inhibits the activation of FLT3-ITD-F691I and its downstream signal proteins such as STAT5 (Figure 2B). Reference: Transl Oncol. 2020 Apr;13(4):100766. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32247263/
In vivo activity: The antitumor efficacy in vivo of GZD824 was also evaluated in MV4–11Flt3-ITD, Ba/F3- FLT3-ITDF691I and KG-1 FGFR1OP2-FGFR1 cells using CB17-SCID mouse xenograft models. The animals were repeatedly administrated vehicle or GZD824 once every 2 days via oral gavage (10 and 20 mg/kg, q2d) for 16 consecutive days. GZD824 was well tolerated in all of the tested groups with no mortality or significant side effects observed during treatment (Tables S2, S3). It was shown that the GZD824 almost completely eradicates xenograft tumors of MV4–11 and KG-1 at a dose of 10 or 20 mg/kg respectively (Figure 5, A, C, E). WB assays in the tumor tissue showed that GZD824 suppresses the FLT3 and FGFR1 activation and induces apoptosis in MV4–11Flt3-ITD, Ba/F3- FLT3-ITDF691I and KG-1 FGFR1OP2-FGFR1 xenograft model (Figure 5, E and F). Reference: Transl Oncol. 2020 Apr;13(4):100766. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32247263/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 80.0 150.30

Preparing Stock Solutions

The following data is based on the product molecular weight 532.22 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:
In vitro protocol: 1. Wang Y, Zhang L, Tang X, Luo J, Tu Z, Jiang K, Ren X, Xu F, Chan S, Li Y, Zhang Z, Ding K. GZD824 as a FLT3, FGFR1 and PDGFRα Inhibitor Against Leukemia In Vitro and In Vivo. Transl Oncol. 2020 Apr;13(4):100766. doi: 10.1016/j.tranon.2020.100766. Epub 2020 Apr 1. PMID: 32247263; PMCID: PMC7125355. 2. Ren X, Pan X, Zhang Z, Wang D, Lu X, Li Y, Wen D, Long H, Luo J, Feng Y, Zhuang X, Zhang F, Liu J, Leng F, Lang X, Bai Y, She M, Tu Z, Pan J, Ding K. Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. J Med Chem. 2013 Feb 14;56(3):879-94. doi: 10.1021/jm301581y. Epub 2013 Jan 28. PMID: 23301703.
In vivo protocol: 1. Wang Y, Zhang L, Tang X, Luo J, Tu Z, Jiang K, Ren X, Xu F, Chan S, Li Y, Zhang Z, Ding K. GZD824 as a FLT3, FGFR1 and PDGFRα Inhibitor Against Leukemia In Vitro and In Vivo. Transl Oncol. 2020 Apr;13(4):100766. doi: 10.1016/j.tranon.2020.100766. Epub 2020 Apr 1. PMID: 32247263; PMCID: PMC7125355. 2. Ren X, Pan X, Zhang Z, Wang D, Lu X, Li Y, Wen D, Long H, Luo J, Feng Y, Zhuang X, Zhang F, Liu J, Leng F, Lang X, Bai Y, She M, Tu Z, Pan J, Ding K. Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. J Med Chem. 2013 Feb 14;56(3):879-94. doi: 10.1021/jm301581y. Epub 2013 Jan 28. PMID: 23301703.

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1: Tang H, Jia W, Jia S, Dong R, Gao S, Feng J, Dong H, Gu H, Zhang T, Yuan R, Liu X, Cheng L, Zhou S, Gao G. A new chemotherapy-free regimen of olverembatinib in combination with venetoclax and dexamethasone for newly diagnosed Ph+ acute lymphoblastic leukemia: Preliminary outcomes of a prospective study. Am J Hematol. 2024 Mar 14. doi: 10.1002/ajh.27289. Epub ahead of print. PMID: 38482543.


2: Zhu H, Hixson P, Ma W, Sun J. Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM. Cell Discov. 2024 Jan 23;10(1):10. doi: 10.1038/s41421-023-00639-8. Erratum in: Cell Discov. 2024 Feb 26;10(1):23. PMID: 38263358; PMCID: PMC10805800.


3: Sanz Murillo M, Villagran Suarez A, Dederer V, Chatterjee D, Alegrio Louro J, Knapp S, Mathea S, Leschziner AE. Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures. Sci Adv. 2023 Dec;9(48):eadk6191. doi: 10.1126/sciadv.adk6191. Epub 2023 Dec 1. PMID: 38039358; PMCID: PMC10691770.


4: Ding J, Li W. Case report: Olverembatinib monotherapy: the chemotherapy-free regimen for an elderly patient with relapsed Ph-positive acute lymphoblastic leukemia. Front Pharmacol. 2023 Nov 16;14:1320641. doi: 10.3389/fphar.2023.1320641. PMID: 38035030; PMCID: PMC10687180.


5: Fan S, Wang L, Lu Y, Li Z. Olverembatinib combined with blinatumomab in treating T315I-mutated Philadelphia chromosome-positive acute lymphoblastic leukemia: two-case report. Ann Hematol. 2024 Feb;103(2):525-532. doi: 10.1007/s00277-023-05519-5. Epub 2023 Nov 9. PMID: 37940719.


6: Hijiya N, Mauro MJ. Asciminib in the Treatment of Philadelphia Chromosome- Positive Chronic Myeloid Leukemia: Focus on Patient Selection and Outcomes. Cancer Manag Res. 2023 Aug 23;15:873-891. doi: 10.2147/CMAR.S353374. PMID: 37641687; PMCID: PMC10460573.


7: Yan Y, Qu S, Liu J, Li C, Yan X, Xu Z, Qin T, Jia Y, Pan L, Gao Q, Jiao M, Li B, Gale RP, Xiao Z. Olverembatinib for myeloid/lymphoid neoplasm associated with eosinophilia and FGFR1 rearrangement. Leuk Lymphoma. 2023 Sep;64(9):1605-1610. doi: 10.1080/10428194.2023.2226277. Epub 2023 Jun 24. PMID: 37354441.


8: Li X, Zhang J, Liu F, Liu T, Zhang R, Chen Y, Guo Y, Fang Y, Xu X, Pui CH, Zhu X. Olverembatinib Treatment in Pediatric Patients With Relapsed Philadelphia-Chromosome-Positive Acute Lymphoblastic Leukemia. Clin Lymphoma Myeloma Leuk. 2023 Sep;23(9):660-666. doi: 10.1016/j.clml.2023.04.012. Epub 2023 May 11. PMID: 37301632.


9: Senapati J, Sasaki K, Issa GC, Lipton JH, Radich JP, Jabbour E, Kantarjian HM. Management of chronic myeloid leukemia in 2023 - common ground and common sense. Blood Cancer J. 2023 Apr 24;13(1):58. doi: 10.1038/s41408-023-00823-9. PMID: 37088793; PMCID: PMC10123066.


10: Liu C, Zhang X, Mao L, Qian J, Xiao F, Ye X, Wei J, Ye X, Jin J, Yu W. Olverembatinib in relapsed Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia: a study of 5 cases. Leuk Lymphoma. 2023 Jun;64(6):1208-1211. doi: 10.1080/10428194.2023.2197534. Epub 2023 Apr 17. PMID: 37067187.


11: Xiang D, Zhao T, Wang J, Cao Y, Yu Q, Liu L, Yu H, Li X, Li N, Yi Y, Gong X. Determination of olverembatinib in human plasma and cerebrospinal fluid by an LC-MS/MS method: Validation and clinical application. J Pharm Biomed Anal. 2023 Jun 15;230:115382. doi: 10.1016/j.jpba.2023.115382. Epub 2023 Mar 31. PMID: 37060798.


12: Scalzulli E, Carmosino I, Costa A, Bisegna ML, Martelli M, Breccia M. Management of Chronic Myeloid Leukemia Patients in Later Lines: The Role of Ponatinib and New Compounds. Clin Lymphoma Myeloma Leuk. 2023 Jun;23(6):420-425. doi: 10.1016/j.clml.2023.03.004. Epub 2023 Mar 20. PMID: 37029061.


13: Yang Z, Liu C, Hu Y, Liu H, Li J, Wu L, Liu Q, Zheng Y, Huang P, Wang Y. Tyrosine kinase inhibitors combined with venetoclax and azacytidine as an effective therapy for de novo lymphoid blast phase-chronic myeloid leukemia. Leuk Res. 2023 Apr;127:107039. doi: 10.1016/j.leukres.2023.107039. Epub 2023 Feb 12. PMID: 36812660.


14: Jiang Q, Li Z, Qin Y, Li W, Xu N, Liu B, Zhang Y, Meng L, Zhu H, Du X, Chen S, Liang Y, Hu Y, Liu X, Song Y, Men L, Chen Z, Niu Q, Wang H, Lu M, Yang D, Zhai Y, Huang X. Correction: Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial. J Hematol Oncol. 2023 Feb 20;16(1):13. doi: 10.1186/s13045-023-01414-8. Erratum for: J Hematol Oncol. 2022 Aug 18;15(1):113. PMID: 36803531; PMCID: PMC9942283.


15: Zhang T, Zhou H, Xu M, Qian C, Sun A, Wu D, Xue S. Combination venetoclax and olverembatinib (HQP1351) as a successful therapeutic strategy for relapsed/refractory (R/R) mixed-phenotype blast phase of chronic myeloid leukemia. Ann Hematol. 2023 Apr;102(4):973-975. doi: 10.1007/s00277-023-05110-y. Epub 2023 Feb 6. PMID: 36745193.


16: Tan X, Wen Q, Chen G, Wan K, Liu X, Ma YY, Wang MH, Zhang X, Zhang C. Novel third-generation tyrosine kinase inhibitor for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: a case study. Anticancer Drugs. 2023 Apr 1;34(4):599-604. doi: 10.1097/CAD.0000000000001455. Epub 2022 Nov 21. PMID: 36730312; PMCID: PMC9997626.


17: Yin Z, Liao M, Yan R, Li G, Ou R, Liu Z, Zhong Q, Shen H, Zhu Y, Xie S, Zhang Q, Liu S, Huang J. Transcriptome- and metabolome-based candidate mechanism of BCR-ABL-independent resistance to olverembatinib in Philadelphia chromosome- positive acute lymphoblastic leukemia. Funct Integr Genomics. 2023 Jan 31;23(1):53. doi: 10.1007/s10142-023-00980-x. PMID: 36717477.


18: Yu Z, Lei Z, Yao X, Wang H, Zhang M, Hou Z, Li Y, Zhao Y, Li H, Liu D, Zhai Y. Potential drug-drug interaction of olverembatinib (HQP1351) using physiologically based pharmacokinetic models. Front Pharmacol. 2022 Dec 13;13:1065130. doi: 10.3389/fphar.2022.1065130. PMID: 36582520; PMCID: PMC9792776.


19: Qian H, Gang D, He X, Jiang S. A review of the therapeutic role of the new third-generation TKI olverembatinib in chronic myeloid leukemia. Front Oncol. 2022 Dec 8;12:1036437. doi: 10.3389/fonc.2022.1036437. PMID: 36568202; PMCID: PMC9772831.


20: Öziskender R, Eşkazan AE. Olverembatinib in chronic myeloid leukemia. Drugs Today (Barc). 2022 Nov;58(11):531-538. doi: 10.1358/dot.2022.58.11.3441854. PMID: 36422514.