DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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AB 680
C20H24ClFN4O9P2, 580.827 g/mol
Cas 2105904-82-1
1H-Pyrazolo[3,4-b]pyridin-4-amine, 6-chloro-N-[(1S)-1-(2-fluorophenyl)ethyl]-1-[5-O-[hydroxy(phosphonomethyl)phosphinyl]-β-D-ribofuranosyl]-
[[(2R,3S,4R,5R)-5-[6-chloro-4-[[(1S)-1-(2-fluorophenyl)ethyl]amino]pyrazolo[3,4-b]pyridin-1-yl]-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]methylphosphonic acid
[({[(2R,3S,4R,5R)-5-(6-chloro-4-{[(1S)-1-(2-fluorophenyl)ethyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic Acid
- Originator C
- Class Antineoplastics; Small molecules
- Mechanism of Action 5-nucleotidase inhibitors; Adenosine A2 receptor antagonists
- Phase I Cancer
- 19 Nov 2018 Arcus Biosciences plans to initiate a clinical trial in Cancer in first half of 2019
- 16 Oct 2018 Phase-I clinical trials in Cancer (In volunteers) in Australia (IV) (NCT03677973)
- 30 Sep 2018 Preclinical pharmacodynamics data in Cancer presented at 4th CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CRI-CIMT-EATI-AACR – 2018)
Clip
Presenter: Kenneth V. Lawson, senior scientist at Arcus Biosciences
Target: Ecto-5’-nucleotidase (CD73)
Disease: Cancer
Reporter’s notes: In the first talk of the day, Lawson introduced the idea of cancer drugs that target the host’s immune system. “Checkpoint inhibitors changed the way we think of treating cancer,” he said. These drugs successfully disrupt the binding interaction between a protein and a checkpoint protein that stops immune T cells from killing cancer cells. As a result, these drugs turn immune cells loose to attack tumor cells. But the drugs work only in about 30-40% of patients—an issue pharmaceutical companies like Arcus hope to address with new immunotherapies that can be taken in combination with checkpoint inhibitors.
Lawson’s team set out to inhibit an enzyme commonly found in tumors called CD73, the second of two enzymes which break down extracellular adenosine trisphosphate (ATP) to adenosine. Adenosine then binds to immunosuppressive receptors on immune cells and shuts them down. Yet developing a small molecule inhibitor of CD73 proved challenging, Lawson said. After striking out with high-throughput screening, the team turned to CD73’s natural substrate for inspiration. However, the molecule possessed more than one phosphate group, which is notoriously a liability for drug molecules because small molecules with such negative changes struggle to cross cell membranes. The team’s goal was to remove the phosphate groups, Lawson says, but things didn’t exactly go according to plan. After showing the audience a series of compounds from structure-activity relationship (SAR) studies—slides no medicinal chemistry talk would be complete without—Lawson revealed the structure of their final clinical compound AB680 as the sound of people flipping notebook sheets rippled across the room. Synthesized in 34% overall yield, the candidate ultimately included two phosphate groups—a feature that surprised audience members.
Tests revealed that AB680 can be given intravenously but the compound also showed moderate oral bioavailability. Lawson suggested a possible route for how the molecule might pass from the digestive tract to the bloodstream, a paracellular mechanism by which molecules cross the epithelium by passing through the space between cells. AB680 showed “extraordinary potency,” inhibiting CD73 in human T-cells at a concentration of 0.008 nM. The compound has a 4 day half-life, which means it could be dosed every two weeks, coinciding with the dosing schedule for patients who receive a checkpoint inhibitor. AB680 is currently in Phase 1 clinical trials with healthy patients.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US204141996&tab=PCTDESCRIPTION&maxRec=1000
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Purinergic signaling, a type of extracellular signaling mediated by purine nucleotides and nucleosides such as ATP and adenosine, involves the activation of purinergic receptors in the cell and/or in nearby cells, resulting in the regulation of cellular functions. Most cells have the ability to release nucleotides, which generally occurs via regulated exocytosis (see Praetorius, H. A.; Leipziger, J. (1 Mar. 2010) Ann Rev Physiology 72(1): 377-393). The released nucleotides can then be hydrolyzed extracellularly by a variety of cellular membrane-bound enzymes referred to as ectonucleotidases.
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Example 92
Synthesis of [({[(2R,3S,4R,5R)-5-(6-chloro-4-{[(1S)-1-(2-fluorophenyl)ethyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic Acid
PATENT
////////////////ARCUS, AB 680, AB680, AB-680, PHASE 1
https://www.arcusbio.com/wp-content/uploads/2018/04/AACR_AB680_1756_final_90x42-abstract-4886.pdf
Fc1ccccc1[C@H](C)Nc4cc(Cl)nc3c4cnn3[C@@H]2O[C@H](COP(=O)(O)CP(=O)(O)O)[C@@H](O)[C@H]2O
CC(C1=CC=CC=C1F)NC2=CC(=NC3=C2C=NN3C4C(C(C(O4)COP(=O)(CP(=O)(O)O)O)O)O)Cl
New Drug Approvals 