ARV-825 - CAS 1818885-28-7

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ARV-825 is a BRD4 inhibitor based on PROTAC technology. ARV-825 recruits BRD4 to E3 ubiquitin ligase cereblon, resulting in the degradation of BRD4. In post-myeloproliferative neoplasm secondary (s) AML cell lines, treatment with ARV-825 induces apoptosis and inhibits cell proliferation.

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Molecular Formula C46H47ClN8O9S
Molecular Weight 923.439

ARV-825

Purity ≥98%
Appearance Yellow to Pale Yellow Powder
Synonyms 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide
Solubility Soluble in DMSO.
Storage -20°C
Shelf Life 2 years
Density 1.47±0.1 g/cm3
InChI Key RWLOGRLTDKDANT-TYIYNAFKSA-N
InChI InChI=1S/C46H47ClN8O9S/c1-26-27(2)65-46-39(26)41(29-7-9-30(47)10-8-29)50-35(42-53-52-28(3)54(42)46)25-38(57)49-31-11-13-32(14-12-31)64-24-23-63-22-21-62-20-19-61-18-17-48-34-6-4-5-33-40(34)45(60)55(44(33)59)36-15-16-37(56)51-43(36)58/h4-14,35-36,48H,15-25H2,1-3H3,(H,49,57)(H,51,56,58)/t35-,36?/m0/s1
Canonical SMILES CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)NC4=CC=C(C=C4)OCCOCCOCCOCCNC5=CC=CC6=C5C(=O)N(C6=O)C7CCC(=O)NC7=O)C8=CC=C(C=C8)Cl)C
1.Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.
Saenz DT;Fiskus W;Qian Y;Manshouri T;Rajapakshe K;Raina K;Coleman KG;Crew AP;Shen A;Mill CP;Sun B;Qiu P;Kadia TM;Pemmaraju N;DiNardo C;Kim MS;Nowak AJ;Coarfa C;Crews CM;Verstovsek S;Bhalla KN Leukemia. 2017 Sep;31(9):1951-1961. doi: 10.1038/leu.2016.393. Epub 2017 Feb 2.
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells.
2.PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy.
Tarantelli C;Gaudio E;Arribas AJ;Kwee I;Hillmann P;Rinaldi A;Cascione L;Spriano F;Bernasconi E;Guidetti F;Carrassa L;Pittau RB;Beaufils F;Ritschard R;Rageot D;Sele A;Dossena B;Rossi FM;Zucchetto A;Taborelli M;Gattei V;Rossi D;Stathis A;Stussi G;Broggini M;Wymann MP;Wicki A;Zucca E;Cmiljanovic V;Fabbro D;Bertoni F Clin Cancer Res. 2018 Jan 1;24(1):120-129. doi: 10.1158/1078-0432.CCR-17-1041. Epub 2017 Oct 24.
Purpose:; Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the ;in vitro; and ;in vivo; activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.;Experimental Design:; This study included preclinical ;in vitro; activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on ;in vivo; models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.;Results:; PQR309 had ;in vitro; antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action.
3.BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells.
Sun B;Fiskus W;Qian Y;Rajapakshe K;Raina K;Coleman KG;Crew AP;Shen A;Saenz DT;Mill CP;Nowak AJ;Jain N;Zhang L;Wang M;Khoury JD;Coarfa C;Crews CM;Bhalla KN Leukemia. 2018 Feb;32(2):343-352. doi: 10.1038/leu.2017.207. Epub 2017 Jun 30.
Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-κB (NF-κB) target genes that undermines the growth and survival of mantle cell lymphoma (MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-κB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells.

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