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Purity: ≥98%
Olverembatinib (GZD824; HQP1351; trade name in China: Nailike) is an orally bioavailable, 3rd generation, and broad spectrum Bcr-Abl inhibitor that received approval in November 2021 in China for the treatment of adult patients with tyrosine kinase inhibitor (TKI)-resistant chronic phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation. Bcr-Abl(WT) and Bcr-Abl(T315I) are inhibited by it, with IC50 values of 0.68 nM and 0.34 nM, respectively. With K(d) values of 0.32 and 0.71 nM, respectively, GZD824 bound to Bcr-Abl(WT) and Bcr-Abl(T315I) tightly and strongly inhibited the kinase functions with nanomolar IC(50) values. The Bcr-Abl-positive K562 and Ku812 human CML cells were potently suppressed in their proliferation by GZD824, with IC(50) values of 0.2 and 0.13 nM, respectively. For the purpose of developing Bcr-Abl inhibitors to overcome acquired imatinib resistance, GZD824 is a fresh and promising lead candidate.
| Targets |
Bcr-AblT315I (IC50 = 0.68 nM); Bcr-AblE255K (IC50 = 0.27 nM); Bcr-AblG250E (IC50 = 0.71 nM); Bcr-AblQ252H (IC50 = 0.15 nM); Bcr-AblH396P (IC50 = 0.35 nM); Bcr-AblM351T (IC50 = 0.29 nM); Bcr-AblY253F (IC50 = 0.35 nM); Bcr-AblF317L
- Breakpoint cluster region-Abelson (Bcr-Abl) kinase (IC₅₀ = 0.34 nM for wild-type, 0.68 nM for T315I mutant) [1] - Phosphorylated and nonphosphorylated Bcr-Abl (KD = 0.32 nM for nonphosphorylated Abl, 0.34 nM for phosphorylated Abl) [1] |
|---|---|
| ln Vitro |
GZD824 has an IC50 of 1.0 nM and potently suppresses the growth of Ba/F3 cells that express wildtype Bcr-Abl. GZD824 also significantly inhibits the proliferation of Ba/F3 cells expressing the Bcr-AblT315I mutant and 14 other resistance-relevant Bcr-Abl mutants, which is highly consistent with biochemical kinase inhibition and tight protein binding affinity. Furthermore, in K562 CML cells, GZD824 effectively and concentration-dependently inhibits the activation of Bcr-Abl as well as downstream Crkl and STAT5.
- Kinase inhibition: Olverembatinib Dimesylate (GZD824) potently inhibited Bcr-Abl kinase activity with nanomolar IC₅₀ values against wild-type (0.34 nM) and T315I mutant (0.68 nM) enzymes. It also suppressed 14 other clinically relevant Bcr-Abl mutants (e.g., E255K, G250E, Q252H) with IC₅₀ values ranging from 0.15–0.71 nM [1] - Cell proliferation: The compound inhibited proliferation of Bcr-Abl-positive leukemia cell lines (K562, Ku-812, Ba/F3) with IC₅₀ values of 0.2–10.8 nM. It induced caspase-dependent apoptosis in K562 cells, as evidenced by cleaved PARP and activated caspase-3 [1] - Signaling pathway: GZD824 blocked Bcr-Abl-mediated phosphorylation of downstream effectors (e.g., CrkL, STAT5) in K562 cells, disrupting oncogenic signaling cascades [1] |
| ln Vivo |
GZD824, without significant body loss or mortality, dose-dependently inhibits the growth of tumors in the K562 tumor xenograft and the Ku812 xenograft model at doses of 5 and 10 mg/kg/day. Additionally, GZD824 (20 mg/kg/day) inhibits the growth of tumors in mice that have allografted Ba/F3 cells that express Bcr-AblWT and Bcr-AblT315I.
- Xenograft models: Oral administration of GZD824 (5–20 mg/kg) dose-dependently suppressed tumor growth in mice bearing K562 (wild-type Bcr-Abl) or Ba/F3-T315I (mutant Bcr-Abl) xenografts. Complete tumor regression was observed in some cases, with no significant toxicity [1] - Survival benefit: In a murine allograft leukemia model, GZD824 (20 mg/kg) improved survival by 100% compared to vehicle controls, preserving hematopoietic stem cell function [1] |
| Enzyme Assay |
ABL1, ABL1(E255K), ABL1 (G250E), ABL1(T315I), and ABL1(Y253F) are histidine-tagged full-length human recombinant proteins that are expressed in insect cells. The kinases PV3864, PV3865, PV3866, and PV3863 are P3049. Utilizing the FRET-based Z′-Lyte assay system, inhibitory activities against Abl1 and its mutants are carried out in 384-well plates. In summary, 5 μL of kinase reaction buffer is mixed with the diluted kinase substrate before the kinase is added. Following the delivery of compounds (10 nL) at the indicated concentrations to the reaction via the Echo liquid handler, the mixture is allowed to sit at room temperature for 30 minutes. Following the addition of 5 μL of 2X ATP solution to start the reaction, the mixture is left to sit at room temperature for an additional two hours. The ensuing reactions contain 10 μM of ATP (for wild-type Abl1, and mutants Y253F, Q252H, M351T, and H396P) or 5 μM (for mutants E255K, G250E, and T315I) of Tyr2 Peptide substrate in 50 mM HEPES (PH 7.5), 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 0.0247 μg/mL Abl1, and inhibitors as needed. Next, add 5 μL of the development reagent, and let the mixture sit at room temperature for two hours before adding 5 μL of the stop solution. With an EnVision Multilabel Reader, the fluorescence signal ratio of 445 nm (Coumarin)/520 nm (fluorescin) is measured. To analyze the data, Graphpad Prism5 is used. The three experiments' mean values make up the data.
- Bcr-Abl kinase activity: Kinase assays were performed using a FRET-based Z′-Lyte system. Recombinant Bcr-Abl enzymes (wild-type or mutants) were incubated with GZD824 and ATP, followed by addition of a fluorescent peptide substrate. Phosphorylation was detected by fluorescence resonance energy transfer, with IC₅₀ values calculated from dose-response curves [1] - Binding affinity: Surface plasmon resonance (SPR) analysis revealed GZD824 bound to nonphosphorylated and phosphorylated Abl with high affinity (KD = 0.32–0.34 nM), competing with ATP at the kinase active site [1] |
| Cell Assay |
In 96-well culture dishes, cells (Ba/F3 cells expressing wildtype and mutant Bcr-Abl) are plated during the logarithmic phase. Cells are treated with the corresponding compounds or vehicle control at the indicated concentration for 72 hours after the 24-hour mark. After adding 10 μL of CCK-8 per well to the 96-well plates, the cells are incubated for three hours. A microplate reader determines OD450 and OD650. The formula for calculating each well's absorbance rate (A) is OD450 - OD650. Each well's cell viability rate is determined by applying the formula V% = (As – Ac)/(Ab – Ac) × 100%. Graphpad Prism5 was utilized to further analyze the data. The three experiments' mean values make up the data. In the test compound well, As is the absorbance rate; in the well without either the test compound or the cell, Ac is the absorbance rate; and in the well with cell and vehicle control, Ab is the absorbance rate.
- Proliferation and apoptosis: Bcr-Abl-positive cells (e.g., K562, Ba/F3) were treated with GZD824 for 72 hours. Cell viability was measured by CCK-8 assay, while apoptosis was assessed by Annexin V/PI staining and Western blot for cleaved caspase-3 and PARP [1] - Signaling pathway analysis: Western blot analysis of K562 cell lysates treated with GZD824 showed dose-dependent reduction in Bcr-Abl phosphorylation and downstream signaling molecules (e.g., p-CrkL, p-STAT5) [1] |
| Animal Protocol |
SCID nude mice, bearing allografted Ba/F3 cells expressing Bcr-AblT315I
1 mg/kg, 2 mg/kg, 5.0 mg/kg, 10 mg/kg, 20 mg/kg Oral gavage, daily, for 10 days - Xenograft model: Nude mice bearing K562 or Ba/F3-T315I tumors received GZD824 orally at 5–20 mg/kg daily. Tumor volume was measured twice weekly, and tissues were harvested for immunohistochemical analysis of Bcr-Abl phosphorylation [1] - Allograft leukemia model: Mice injected with Ba/F3-T315I cells were treated with GZD824 (20 mg/kg, oral) starting 24 hours post-implantation. Survival was monitored daily for 35 days [1] |
| ADME/Pharmacokinetics |
- Oral bioavailability: GZD824 exhibited moderate oral bioavailability (48.7%) in mice, with a plasma half-life of 10.6 hours [1]
- Tissue distribution: The drug achieved high concentrations in tumor tissues, with a tumor-to-plasma concentration ratio of 2.1 [1] |
| Toxicity/Toxicokinetics |
- No significant toxicity: In murine studies, GZD824 at doses up to 20 mg/kg did not cause mortality or significant body weight loss, indicating favorable tolerability [1]
|
| References | |
| Additional Infomation |
HQP1351 is under investigation in clinical trial NCT03883100 (A Pivotal Study of HQP1351 in Patients of Chronic Myeloid Leukemia in Accelerated Phase With T315I Mutation).
Olverembatinib is an orally bioavailable inhibitor of a variety of kinases, including the Bcr-Abl tyrosine kinase, the mast/stem cell growth factor receptor Kit (c-Kit), the serine/threonine protein kinase Akt (protein kinase B), and the extracellular signal-regulated kinase (ERK) with antineoplastic activity. Upon administration,olverembatinib targets, binds to and inhibits the kinase activities of Bcr-Abl, AKT, c-Kit and ERK. This inhibits their mediated signaling pathways and inhibits proliferation of tumor cells in which these kinases are overexpressed and/or mutated. Bcr-Abl, c-Kit, AKT and ERK play key roles in the proliferation, differentiation and survival of tumor cells. - Mechanism: GZD824 binds to the ATP-binding pocket of Bcr-Abl, preventing kinase activation and downstream signaling. Its dual targeting of phosphorylated and nonphosphorylated states ensures broad efficacy against resistant mutants [1] - Therapeutic potential: The compound demonstrated efficacy against imatinib-resistant CML in preclinical models, supporting its development as a third-generation Bcr-Abl inhibitor [1] |
| Molecular Formula |
C29H27F3N6O
|
|---|---|
| Molecular Weight |
532.22
|
| Exact Mass |
532.219
|
| Elemental Analysis |
C, 65.40; H, 5.11; F, 10.70; N, 15.78; O, 3.00
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| CAS # |
1257628-77-5
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| Related CAS # |
Olverembatinib dimesylate;1421783-64-3
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| PubChem CID |
51038269
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
630.4±55.0 °C at 760 mmHg
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| Flash Point |
335.0±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.667
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| LogP |
3.93
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
39
|
| Complexity |
910
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O=C(NC1=CC=C(CN2CCN(C)CC2)C(C(F)(F)F)=C1)C3=CC=C(C)C(C#CC4=CN=C(NN=C5)C5=C4)=C3
|
| InChi Key |
TZKBVRDEOITLRB-UHFFFAOYSA-N
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| 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)
|
| Chemical Name |
4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide
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| Synonyms |
GZD824; Olverembatinib; GZD 824; 1257628-77-5; olverembatinib; 3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; HQP1351; 4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide; KV1M7Q3CBP; HQP-1351; Benzamide, 4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]-; HQP1351; GZD-824; HQP-1351; Nailike
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (5.16 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.75 mg/mL (5.16 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.75 mg/mL (5.16 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8789 mL | 9.3946 mL | 18.7892 mL | |
| 5 mM | 0.3758 mL | 1.8789 mL | 3.7578 mL | |
| 10 mM | 0.1879 mL | 0.9395 mL | 1.8789 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06051409 | Recruiting | Drug: Olverembatinib Drug: Imatinib |
Ph+ ALL | Ascentage Pharma Group Inc. | September 2, 2023 | Phase 3 |
| NCT05311943 | Recruiting | Drug: olverembatinib | Olverembatinib Tyrosine Kinase Inhibitors |
Shenzhen Second People's Hospital | July 1, 2022 | Phase 3 |
| NCT05931757 | Not yet recruiting | Drug: Olverembatinib | Philadelphia-Positive ALL | The First Affiliated Hospital of Soochow University |
July 1, 2023 | Phase 2 |
| NCT05466175 | Not yet recruiting | Drug: Olverembatinib Drug: Prednisone |
Philadelphia-Positive ALL | Chen Suning | October 1, 2022 | Phase 2 |
| NCT05521204 | Recruiting | Drug: Olverembatinib | Myeloproliferative Neoplasm Acute Leukemia |
The First Affiliated Hospital of Soochow University |
September 1, 2022 | Phase 2 |
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