| Chemical Properties | Back Directory | [density ]
1.48±0.1 g/cm3(Predicted) | [solubility ]
Soluble to 100 mM in DMSO | [form ]
Solid | [pka]
10.68±0.40(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Uses]
XY-06-007 is a selective and potent bump-and-hole (B&H)-PROTAC BRD4BD1L94V degrader. XY-06-007 shows a DC50, 6 h of 10 nM against BRD4BD1L94V with no degradation of off-targets. XY-06-007 demonstrates suitable pharmacokinetics for in vivo studies[1]. | [Biological Activity]
XY-06-007 is a highly selective and potent "Bump & Hole" TAG Degrader (DC50,6h = 10 nM, T1/2 < 43.2 min). XY-06-007 comprises a cereblon (CRBN) E3 ligase ligand joined by a linker to a (+)-JQ1 derivative (the "bump" bearer) that selectively binds the Brd4BD1 L94V variant (the "hole"). In cell lines expressing a fusion of the target protein with the tag, Brd4BD1 L94V, XY-06-007 drives formation of a ternary complex between CRBN and the tagged protein, leading to ubiquitination and subsequent proteasomal degradation of the entire protein. XY-06-007 is highly selective for Brd4BD1 L94V over wild-type, and is broadly selective across the proteome. XY-06-007 can be combined with the dTAG approach to achieve simultaneous degrader-mediated depletion of their respective protein fusions. XY-06-007 is suitable for in vivo studies. | [in vivo]
XY-06-007 has favorable pharmacokinetic profile, including good plasma concentration, area under the curve (AUC), and bioavailability. XY-06-007 exhibits short elimination half-life (0.515 h) due to relatively low clearance (21.9 mL/min/kg) following intravenous administration (2.0 mg/kg). XY-06-007 exhibits short elimination half-life (0.721 h) due to the Cmax (6.10 μM) and Tmax (0.25 h) following intraperitoneal injection (10 mg/kg)[1]. | Animal Model: | Six to eight weeks old male C57BL/6 mice[1] | | Dosage: | 2 mg/kg (iv) or 10 mg/kg (ip) (Pharmacokinetic Analysis) | | Administration: | Administered via tail vein injection or via intraperitoneal injection. Approximately 110 μL of blood/time point was collected into the K2EDTA tube via facial vein for bleeding for the time points: 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h. | | Result: | Maintained above its DC50, 6h of 10 nM for approximately 6 h when dosed at 10 mg/kg via intraperitoneal injection (IP), indicating that such in vivo degradation experiment would result in a favorable outcome. |
| [IC 50]
Cereblon | [storage]
Store at -20°C | [References]
[1] Rados?aw P Nowak, et al. Structure-Guided Design of a "Bump-and-Hole" Bromodomain-Based Degradation Tag. J Med Chem. 2021 Aug 12;64(15):11637-11650. DOI:10.1021/acs.jmedchem.1c00958 |
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