WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H561105
CAS#: 1637771-14-2
Description: Alobresib, also known as GS-5829, is a potent and selective BET inhibitor. GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment. GS-5829 inhibited CLL cell proliferation and induced leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. IκBα modulation indicates that GS-5829 also inhibited NF-κB signaling. GS-5829-induced apoptosis resulted from an imbalance between positive (BIM) and negative regulators (BCL-XL) of the intrinsic apoptosis pathway.
Hodoodo Cat#: H561105
Name: Alobresib
CAS#: 1637771-14-2
Chemical Formula: C26H23N5O2
Exact Mass: 437.19
Molecular Weight: 437.500
Elemental Analysis: C, 71.38; H, 5.30; N, 16.01; O, 7.31
Synonym: Alobresib; GS-5829; GS 5829; GS5829;
IUPAC/Chemical Name: [2-cyclopropyl-6-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-4-yl]di(pyridin-2-yl)methanol
InChi Key: CMSUJGUHYXQSOK-UHFFFAOYSA-N
InChi Code: InChI=1S/C26H23N5O2/c1-15-23(16(2)33-31-15)18-13-19(24-20(14-18)29-25(30-24)17-9-10-17)26(32,21-7-3-5-11-27-21)22-8-4-6-12-28-22/h3-8,11-14,17,32H,9-10H2,1-2H3,(H,29,30)
SMILES Code: OC(C1=NC=CC=C1)(C2=C3N=C(C4CC4)NC3=CC(C5=C(C)ON=C5C)=C2)C6=NC=CC=C6
Appearance: 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
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: The antileukemia activity of GS-5829 increased synergistically in combinations with B-cell receptor signaling inhibitors, the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, and the SYK inhibitor entospletinib. In cocultures that mimic the lymph node microenvironment, GS-5829 inhibited signaling pathways within nurselike cells and their growth, indicating that BET inhibitors also can target the supportive CLL microenvironment.
| Biological target: | Alobresib (GS-5829) is a BET bromodomain inhibitor. |
| In vitro activity: | GS-5829 inhibited CLL cell proliferation and induced leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. IκBα modulation indicates that GS-5829 also inhibited NF-κB signaling. GS-5829-induced apoptosis resulted from an imbalance between positive (BIM) and negative regulators (BCL-XL) of the intrinsic apoptosis pathway. The antileukemia activity of GS-5829 increased synergistically in combinations with B-cell receptor signaling inhibitors, the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, and the SYK inhibitor entospletinib. In cocultures that mimic the lymph node microenvironment, GS-5829 inhibited signaling pathways within nurselike cells and their growth, indicating that BET inhibitors also can target the supportive CLL microenvironment. Reference: Leukemia. 2020 Jun;34(6):1588-1598. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31862959/ |
| In vivo activity: | Xenografts bearing USC-ARK2 tumors were treated with a single dose of GS-5829 at 40, 20, 10 mg/kg or vehicle through oral gavage and blood samples were collected at different time points for PK and PD studies. As shown in Figure 5, no significant difference in inhibition of c-Myc protein expression were detected at the dose of 10 mg/kg to 40 mg/kg for both drugs, and such inhibition was significantly greater when compared to the control group (ie. vehicle group). Pharmacokinetic analysis of collected plasma showed excellent oral bioavailability for both GS-5829 and GS-626510 in the mouse model (data not shown). The impact of GS-5829 was evaluated in vivo in xenograft models generated by injecting subcutaneously ARK2 cells into female CB17/lcrHsd-Prkd/scid mice. For comparison we also tested the BET inhibitor JQ1, dosed by intraperitoneal injection (50 mg/kg/day). Twice daily oral doses of GS-5829 10 mg/kg and 20 mg/kg were well tolerated with no clear impact on body weight compared with vehicle control. As shown in Figure 6A, mice undergoing twice daily oral treatment with GS-5829 (20 mg/kg and 10 mg/kg) exhibited a significantly slower rate of tumor growth, compared to vehicle control and to mice undergoing daily treatment with JQ1 (50 mg/kg/day IP). This difference was statistically significant starting on dosing day 21 (p value |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 83.3 | 190.47 |
The following data is based on the product molecular weight 437.50 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.
| 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. Kim E, Ten Hacken E, Sivina M, Clarke A, Thompson PA, Jain N, Ferrajoli A, Estrov Z, Keating MJ, Wierda WG, Bhalla KN, Burger JA. The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment. Leukemia. 2020 Jun;34(6):1588-1598. doi: 10.1038/s41375-019-0682-7. Epub 2019 Dec 20. PMID: 31862959; PMCID: PMC7272263. 2. Bonazzoli E, Predolini F, Cocco E, Bellone S, Altwerger G, Menderes G, Zammataro L, Bianchi A, Pettinella F, Riccio F, Han C, Yadav G, Lopez S, Manzano A, Manara P, Buza N, Hui P, Wong S, Litkouhi B, Ratner E, Silasi DA, Huang GS, Azodi M, Schwartz PE, Schlessinger J, Santin AD. Inhibition of BET Bromodomain Proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a Biologically Aggressive Variant of Endometrial Cancer. Clin Cancer Res. 2018 Oct 1;24(19):4845-4853. doi: 10.1158/1078-0432.CCR-18-0864. Epub 2018 Jun 25. PMID: 29941483; PMCID: PMC6168417. |
| In vivo protocol: | 1. Bonazzoli E, Predolini F, Cocco E, Bellone S, Altwerger G, Menderes G, Zammataro L, Bianchi A, Pettinella F, Riccio F, Han C, Yadav G, Lopez S, Manzano A, Manara P, Buza N, Hui P, Wong S, Litkouhi B, Ratner E, Silasi DA, Huang GS, Azodi M, Schwartz PE, Schlessinger J, Santin AD. Inhibition of BET Bromodomain Proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a Biologically Aggressive Variant of Endometrial Cancer. Clin Cancer Res. 2018 Oct 1;24(19):4845-4853. doi: 10.1158/1078-0432.CCR-18-0864. Epub 2018 Jun 25. PMID: 29941483; PMCID: PMC6168417. |
1: Krumova SB, Várkonyi Z, Lambrev PH, Kovács L, Todinova SJ, Busheva MC, Taneva SG, Garab G. Heat- and light-induced detachment of the light-harvesting antenna complexes of photosystem I in isolated stroma thylakoid membranes. J Photochem Photobiol B. 2014 Aug;137:4-12. doi: 10.1016/j.jphotobiol.2014.04.029. Epub 2014 May 16. PMID: 24912404.
2: Alboresi A, Storti M, Cendron L, Morosinotto T. Role and regulation of class-C flavodiiron proteins in photosynthetic organisms. Biochem J. 2019 Sep 13;476(17):2487-2498. doi: 10.1042/BCJ20180648. PMID: 31519856.
3: Alvisi P, Brusa S, Alboresi S, Amarri S, Bottau P, Cavagni G, Corradini B, Landi L, Loroni L, Marani M, Osti IM, Povesi-Dascola C, Caffarelli C, Valeriani L, Agostoni C. Recommendations on complementary feeding for healthy, full-term infants. Ital J Pediatr. 2015 Apr 28;41:36. doi: 10.1186/s13052-015-0143-5. PMID: 25928205; PMCID: PMC4464122.
4: Alboresi A, Storti M, Morosinotto T. Balancing protection and efficiency in the regulation of photosynthetic electron transport across plant evolution. New Phytol. 2019 Jan;221(1):105-109. doi: 10.1111/nph.15372. Epub 2018 Aug 7. PMID: 30084195.
5: Storti M, Costa A, Golin S, Zottini M, Morosinotto T, Alboresi A. Systemic Calcium Wave Propagation in Physcomitrella patens. Plant Cell Physiol. 2018 Jul 1;59(7):1377-1384. doi: 10.1093/pcp/pcy104. PMID: 29878186.
6: Sello S, Meneghesso A, Alboresi A, Baldan B, Morosinotto T. Plant biodiversity and regulation of photosynthesis in the natural environment. Planta. 2019 Apr;249(4):1217-1228. doi: 10.1007/s00425-018-03077-z. Epub 2019 Jan 3. PMID: 30607502.
7: Mellon M, Storti M, Vera-Vives AM, Kramer DM, Alboresi A, Morosinotto T. Inactivation of mitochondrial complex I stimulates chloroplast ATPase in Physcomitrium patens. Plant Physiol. 2021 Oct 5;187(2):931-946. doi: 10.1093/plphys/kiab276. PMID: 34608952; PMCID: PMC8491079.
8: Beraldo C, Guyon-Debast A, Alboresi A, Nogué F, Morosinotto T. Functional analysis of PsbS transmembrane domains through base editing in Physcomitrium patens. Plant J. 2023 Mar;113(5):1049-1061. doi: 10.1111/tpj.16099. Epub 2023 Jan 31. PMID: 36606401.
9: Lu Y, Gan Q, Iwai M, Alboresi A, Burlacot A, Dautermann O, Takahashi H, Crisanto T, Peltier G, Morosinotto T, Melis A, Niyogi KK. Role of an ancient light-harvesting protein of PSI in light absorption and photoprotection. Nat Commun. 2021 Jan 29;12(1):679. doi: 10.1038/s41467-021-20967-1. PMID: 33514722; PMCID: PMC7846763.
10: Storti M, Segalla A, Mellon M, Alboresi A, Morosinotto T. Regulation of electron transport is essential for photosystem I stability and plant growth. New Phytol. 2020 Nov;228(4):1316-1326. doi: 10.1111/nph.16643. Epub 2020 Jun 18. PMID: 32367526.
11: Gerotto C, Alboresi A, Meneghesso A, Jokel M, Suorsa M, Aro EM, Morosinotto T. Flavodiiron proteins act as safety valve for electrons in Physcomitrella patens. Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):12322-12327. doi: 10.1073/pnas.1606685113. Epub 2016 Oct 10. PMID: 27791022; PMCID: PMC5087051.
12: Alboresi A, Ballottari M, Hienerwadel R, Giacometti GM, Morosinotto T. Antenna complexes protect Photosystem I from photoinhibition. BMC Plant Biol. 2009 Jun 9;9:71. doi: 10.1186/1471-2229-9-71. PMID: 19508723; PMCID: PMC2704212.
13: Storti M, Puggioni MP, Segalla A, Morosinotto T, Alboresi A. The chloroplast NADH dehydrogenase-like complex influences the photosynthetic activity of the moss Physcomitrella patens. J Exp Bot. 2020 Sep 19;71(18):5538-5548. doi: 10.1093/jxb/eraa274. PMID: 32497206.
14: De Bortoli S, Teardo E, Szabò I, Morosinotto T, Alboresi A. Evolutionary insight into the ionotropic glutamate receptor superfamily of photosynthetic organisms. Biophys Chem. 2016 Nov;218:14-26. doi: 10.1016/j.bpc.2016.07.004. Epub 2016 Aug 2. PMID: 27586818.
15: Alboresi S, Sghedoni A, Borelli G, Costi S, Beccani L, Neviani R, Ferrari A. Are perceptual disorder signs in diplegic cerebral palsied children stable over time? A retrospective cohort analysis. Minerva Pediatr. 2020 Apr;72(2):79-84. doi: 10.23736/S0026-4946.18.05237-4. Epub 2019 Apr 16. PMID: 30994318.
16: Fainardi V, Caffarelli C, Bergamini BM, Biserna L, Bottau P, Corinaldesi E, Dondi A, Fornaro M, Guidi B, Lombardi F, Magistrali MS, Marastoni E, Piccorossi A, Poloni M, Tagliati S, Vaienti F, Venturelli C, Ricci G, Esposito S; Emilia- Romagna Asthma (ERA) Study Group. Management of Children with Acute Asthma Attack: A RAND/UCLA Appropriateness Approach. Int J Environ Res Public Health. 2021 Dec 3;18(23):12775. doi: 10.3390/ijerph182312775. PMID: 34886505; PMCID: PMC8657661.
17: Floris M, Bassi R, Robaglia C, Alboresi A, Lanet E. Post-transcriptional control of light-harvesting genes expression under light stress. Plant Mol Biol. 2013 May;82(1-2):147-54. doi: 10.1007/s11103-013-0046-z. Epub 2013 Mar 25. PMID: 23526054.
18: Costi S, Mecugni D, Beccani L, Alboresi S, Bressi B, Paltrinieri S, Ferrari A, Pelosin E. Construct Validity of the Activities Scale for Kids Performance in Children with Cerebral Palsy: Brief Report. Dev Neurorehabil. 2020 Oct;23(7):474-477. doi: 10.1080/17518423.2020.1764649. Epub 2020 Jun 7. PMID: 32508188.
19: Bellan A, Bucci F, Perin G, Alboresi A, Morosinotto T. Photosynthesis Regulation in Response to Fluctuating Light in the Secondary Endosymbiont Alga Nannochloropsis gaditana. Plant Cell Physiol. 2020 Jan 1;61(1):41-52. doi: 10.1093/pcp/pcz174. PMID: 31511895.
20: Alboresi A, Perin G, Vitulo N, Diretto G, Block M, Jouhet J, Meneghesso A, Valle G, Giuliano G, Maréchal E, Morosinotto T. Light Remodels Lipid Biosynthesis in Nannochloropsis gaditana by Modulating Carbon Partitioning between Organelles. Plant Physiol. 2016 Aug;171(4):2468-82. doi: 10.1104/pp.16.00599. Epub 2016 Jun 20. PMID: 27325666; PMCID: PMC4972283.
