Overview on physicochemical properties and cellular activities of three-branched CRBN ligands and PROTACs.

Cmpd	log D7.4a	CHIIAMb	% HSA bindingc	K i/Kdd (μM)	DC50e (nM)	% BRD4f deg.
9	1.7	21.1	81	0.2 ± 0.7	n.d.g	n.d.
11	3.2	n.d.	n.d.	11.0 ± 13.5h	n.d.	n.d.
13a	3.1	34.5	94	n.d.	6.1 ± 2.4	95
13b	2.5	29.6	91	n.d.	88 ± 53	38
13c	2.5	29.2	90	n.d.	162 ± 41	22
13d	2.5	28.7	90	n.d.	83 ± 80	52

^aDistribution coefficients at pH 7.4 were estimated by an HPLC-based method.

^bChromatographic hydrophobicity index values referring to IAM chromatography (CHI_IAM values), an estimate for drug-membrane interactions and permeability.²⁸

^cProtein binding values were estimated by an HPLC-based method.

^dAffinity values determined in a competitive MST assay as described in the Method sections (see ESI).

^eConcentration at which 50% of BRD4 has been degraded after 24 h treatment of Namalwa cells with each compound ranging from 0.1 to 1000 nM.

^fPercentage of degraded BRD4 after 24 h treatment of Namalwa cells with 0.1 μM of each compound.

^gNot determined.

^hAffinity was determined as a K_dvia initial fluorescence and is reported in place of the K_i.