7uzn

From Proteopedia

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH BMT-206059 AKA 2-{(3M)-3-(1,4-DIMETHYL-1H-1,2,3-TRIAZOL-5-YL)-8-FLUORO-5-[(S)-(OXAN-4-YL)(PHENYL)METHYL]-5H-PYRIDO[3,2-b]INDOL-7-YL}PROPAN-2-OL, TRIPLY DEUTERATED ON THE 4-METHYL GROUP

Structural highlights

7uzn is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.685Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.^[1] ^[2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

Publication Abstract from PubMed

We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-((2)H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl) (phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.

Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties.,Hill MD, Fang H, Norris D, Delucca GV, Huang H, DeBenedetto M, Quesnelle C, Schmitz WD, Tokarski JS, Sheriff S, Yan C, Fanslau C, Haarhoff Z, Huang C, Kramer M, Madari S, Menard K, Monereau L, Morrison J, Raghavan N, Shields EE, Simmermacher-Mayer J, Sinz M, Tye CK, Westhouse R, Xie C, Zhang H, Zhang L, Zvyaga T, Lee F, Gavai AV, Degnan AP ACS Med Chem Lett. 2022 Jul 5;13(7):1165-1171. doi:, 10.1021/acsmedchemlett.2c00219. eCollection 2022 Jul 14. PMID:35859878^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
↑ Hill MD, Fang H, Norris D, Delucca GV, Huang H, DeBenedetto M, Quesnelle C, Schmitz WD, Tokarski JS, Sheriff S, Yan C, Fanslau C, Haarhoff Z, Huang C, Kramer M, Madari S, Menard K, Monereau L, Morrison J, Raghavan N, Shields EE, Simmermacher-Mayer J, Sinz M, Tye CK, Westhouse R, Xie C, Zhang H, Zhang L, Zvyaga T, Lee F, Gavai AV, Degnan AP. Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties. ACS Med Chem Lett. 2022 Jul 5;13(7):1165-1171. PMID:35859878 doi:10.1021/acsmedchemlett.2c00219