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AB-680 (Quemliclustat; AB680) is novel, exceptionally potent, reversible and selective small molecule inhibitor of CD73 (an ecto-nucleotidase, a Ki of 4.9 pM for hCD73) with anti-tumor activity. It exhibits >10,000-fold selectivity over related ecto-nucleotidases CD39.
| Targets |
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| ln Vitro |
AB-680 (AB680) suppresses soluble hCD73 at an IC50 of 0.043 nM, hCD73 in CHO cells, and CD73 in human and murine CD8+ T cells and hPBMC at IC50s of 0.070, 0.008, 0.66, and 0.011 nM, respectively [1].
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| ln Vivo |
On the basis of the extraordinary potency of AB680 in vitro and excellent pharmacokinetic profile in preclinical species, AB680 was advanced to a phase I clinical study in healthy volunteers. This placebo-controlled study assessed the safety, tolerability, and PK/PD profile of AB680. Here we present the initial pharmacokinetic data of AB680 in humans. AB680 was well tolerated when administered as a single iv dose across the range of 0.1–25 mg (six cohorts). All treatment-emergent adverse events were mild or moderate in severity, with no clear pattern of toxicity at these dose levels. AB680 displayed low clearance and a long half-life (67–74 h) following an iv infusion of 16 or 25 mg over 30–60 min. The human PK profile of AB680 is consistent with the intended Q2W dosing schedule and validates the design strategy employed to discover a long-acting drug for iv-administration.[1]
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| Enzyme Assay |
CYP inhibition procedure: [1]
Test compounds were evaluated in-vitro for its potential to inhibit major human drug metabolizing enzymes of the cytochrome P450 family. The test compounds were incubated separately over a concentration range of 0 to 40 µM with 0.1 mg/mL human liver microsomal protein suspension in 0.1 M potassium phosphate buffer at pH 7.4, 1 mM NADPH, and a probe substrate (Phenacetin for CYP1A2, Diclofenac for CYP2C9, S-Mephenytoin for CYP2C19, Dextromethorphan for CYP2D6, and Midazolam for CYP3A4). Each substrate was incubated at 37 °C for 5 to 20 minutes as defined by the previous assay validation. Samples for each substrate were collected and pooled with samples from other substrate incubations for determination of product formation by LC-MS/MS. IC50 values were calculated using variable slope (4-parameter) model. Furafylline (1A2), sulfaphenazole (2C9), (+)-N-3-Benzylnirvanol (2C19), quinidine (2D6), and ketoconazole (3A4) were used as reference controls. |
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| Cell Assay |
Cellular Human CD73 Assay. [1]
Generation and Expansion of Human CD73 Stable CHO Cell Line. Stable cell lines were generated by Lake Pharma using a standard protocol to transform CHO cells with a pcDNA3.1(+) vector carrying the human NT5E (CD73) gene. Antibiotic selection was performed in CD OptiCHO cell media containing 5 μg / mL Puromycin and 200 μg / mL Hygromycin B. Pools of surviving CHO-CD73 were collected and frozen in 7.5% DMSO in CD OptiCHO cell media. Cryopreserved cells were defrosted in a water bath at 37°C by agitating the vial until the cells were completely thawed. Cells were then transferred to a 15 mL Falcon tube prior to centrifuging at 225xg for 5 minutes to pellet the cells. The cell pellet was resuspended in fresh warm CD OptiCHO Growth Medium supplemented with 2 mM Glutamax and transferred to a T175 flask. After two days and on reaching ~80% confluence (~20 million cells/flask) cells were split 1:3 into three fresh T175 flasks. After a further three days, cells were transferred to a 15 mL Falcon tubes and centrifuged at 250xg for 5 minutes to pellet. Cells were re-suspended at a density of 3 million cells per mL in CellBanker2 cryopreservation media and aliquoted into cryogenic vials. Cell aliquots were stored at -80°C until needed. |
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| Animal Protocol |
Clinical Study[1]
The phase I clinical study was a first-in-human, double-blind, randomized, placebo-controlled combined single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study to evaluate the safety, tolerability, PK, and potential PD effects of AB680 in healthy volunteers. Participants were randomly selected to receive AB680 (n = 6) or matching placebo (n = 2) in each of seven dosing cohorts in the SAD part and a single dose cohort in the MAD part. In the SAD part of the study, participants received a single iv infusion of 0.1, 0.6, 2, 4, 8, 16, 25 mg of AB680 or placebo. In the MAD part of the study, participants received iv infusion of 8 mg of AB680 or placebo once daily on 3 days (days 1, 8, and 15). |
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| ADME/Pharmacokinetics |
The pharmacokinetics (PK) of AB680 were assessed in rodent and non-rodent species. The PK properties of AB680 are characterized by very low clearance and long half-lives in preclinical species, resulting in projected human PK properties suitable for intravenous (i.v.) dosing on a schedule consistent with typical mAb dosing cycles. High-dose infusions of AB680 in preclinical species were well tolerated.[2]
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| References | ||
| Additional Infomation |
Quemliclustat is a small molecule, competitive inhibitor of the ectoenzyme CD73 (cluster of differentiation 73; 5'-ecto-nucleotidase; 5'-NT; ecto-5'-nucleotidase), with potential immunomodulating and antineoplastic activities. Upon administration, quemliclustat targets and binds to CD73, leading to clustering of and internalization of CD73. This prevents CD73-mediated conversion of adenosine monophosphate (AMP) to adenosine and decreases the amount of free adenosine in the tumor microenvironment (TME). This prevents adenosine-mediated lymphocyte suppression and increases the activity of CD8-positive effector cells and natural killer (NK) cells. This also activates macrophages and reduces the activity of myeloid-derived suppressor cells (MDSCs) and regulatory T-lymphocytes (Tregs). By abrogating the inhibitory effect on the immune system and enhancing the cytotoxic T-cell-mediated immune response against cancer cells, tumor cell growth decreases. In addition, clustering and internalization of CD73 decreases the migration of cancer cells and prevents metastasis. CD73, a plasma membrane protein belonging to the 5'-nucleotidase (NTase) family, upregulated on a number of cancer cell types, catalyzes the conversion of extracellular nucleotides, such as AMP, to membrane-permeable nucleosides, such as adenosine; it plays a key role in adenosine-mediated immunosuppression within the TME.
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| Molecular Formula |
C20H24CLFN4O9P2
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|---|---|
| Molecular Weight |
580.824889183044
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| Exact Mass |
580.069
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| Elemental Analysis |
C, 41.36; H, 4.17; Cl, 6.10; F, 3.27; N, 9.65; O, 24.79; P, 10.67
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| CAS # |
2105904-82-1
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| Related CAS # |
AB-680 ammonium
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| PubChem CID |
130205852
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| Appearance |
White to off-white solid powder
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| LogP |
-0.7
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
37
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| Complexity |
893
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| Defined Atom Stereocenter Count |
5
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| SMILES |
ClC1=CC(=C2C=NN(C2=N1)[C@H]1[C@@H]([C@@H]([C@@H](COP(CP(=O)(O)O)(=O)O)O1)O)O)N[C@@H](C)C1C=CC=CC=1F
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| InChi Key |
MFYLCAMJNGIULC-KCVUFLITSA-N
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| InChi Code |
InChI=1S/C20H24ClFN4O9P2/c1-10(11-4-2-3-5-13(11)22)24-14-6-16(21)25-19-12(14)7-23-26(19)20-18(28)17(27)15(35-20)8-34-37(32,33)9-36(29,30)31/h2-7,10,15,17-18,20,27-28H,8-9H2,1H3,(H,24,25)(H,32,33)(H2,29,30,31)/t10-,15+,17+,18+,20+/m0/s1
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| Chemical Name |
(((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluorophenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic
acid
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| Synonyms |
AB680; Quemliclustat; AB 680; Quémliclustat; AB-680; Quemliclustat; 2105904-82-1; AB680; Quemliclustat [USAN]; UNII-J6K8WSV73A; J6K8WSV73A; QUEMLICLUSTAT [INN]; Quemliclustatum; AB-680
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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) |
DMSO : ~200 mg/mL (~344.34 mM)
H2O : ~5 mg/mL (~8.61 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 7.5 mg/mL (12.91 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 75.0 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: ≥ 7.5 mg/mL (12.91 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 75.0 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: ≥ 7.5 mg/mL (12.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (4.30 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: 2.5 mg/mL (4.30 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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. Solubility in Formulation 6: ≥ 0.5 mg/mL (0.86 mM) (saturation unknown) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7217 mL | 8.6085 mL | 17.2170 mL | |
| 5 mM | 0.3443 mL | 1.7217 mL | 3.4434 mL | |
| 10 mM | 0.1722 mL | 0.8609 mL | 1.7217 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.
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