The probe is available from Sigma.

Click here to obtain the control.


The Histone Lysine Methyltransferase (HMT) complex MLL1 is a crucial epigenetic writer to control DNA accessibility and promote gene transcription [1,2]. The complex incorporates WDR5 (WD40-repeat containing protein 5) that acts as scaffolding component and enhances HMT activity of MLL1. [2] The propeller-shaped WDR5 protein contains two binding sites that interact not only with oncogenic drivers like MLL1, but also with various other proteins like the oncoprotein MYC. [3]

Here, we present a new chemical degrader probe for the WDR5 protein, Homer, that was initially designed by the OICR and the SGC Toronto [4, 5] and then further advanced into a PROTAC (Proteolysis targeting chimera) chemical probe by the SGC Frankfurt [6]. This scaffold represents the first chemical degrader probe for WDR5.

Homer binds potently to WDR5 with a K D (ITC) of 18 nM. It is selective as shown in quantitative proteomic studies. This compound is non-toxic as demonstrated by the AlarmarBlue assay in U2OS cells. Homer shows remarkably cellular activity in MV4-11 cells by inducing WDR5 degradation in a catalytic manner a DC 50 of 53 nM. The DC max of Homer is 58% and observed at cellular concentrations of 1 µM.

In addition, two negative control compounds, nc_WDR5 and nc_VHL, are provided, which showed no degradational activity.



Summary of Potency and efficacy of Homer

WDR5Homer KD
DSF13.2 K 
ITC18 nM 
NanoBRET13.6 µM 

DCmax: 58% at 1 µM 

DC50: 53 nM 

quantitative Proteomics (-log10p > 3, log2FC < -0.5) 


Selectivity of the first WDR5 probe OICR-9429 was shown previously [5, 6]. Selectivity for the Homer probe was confirmed by quantitative proteomics.


For optimal degradation and to overcome the Hook effect, we recommend that a concentration of 1 µM should be used in cell-based assays. 

Cellular Activity 

Homer induces depletion of endogenous WDR5 in various cancer cell lines by inducing protein ubiquitylation and degradation. 

Physical and Chemical Properties
Molecular weight1012.16
Molecular formulaC52H60F3N9O7S
IUPAC nameN-(4'-((5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)carbamoyl)-4-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
clogPo/w (SwissADME)5.31
TPSA (SwissADME)237.41 Å2
No. of chiral centres3
No. of rotatable bonds23
No. of hydrogen bond acceptors12
No. of hydrogen bond donors6
Storagestable as powder at -20°C. NB making aliquots rather than freeze-thawing is recommended
Dissolutionsoluble in DMSO at 50 mM


Physical and Chemical Properties
Molecular weight1012.16
Molecular formulaC52H60F3N9O7S
IUPAC nameN-(4'-((5-(((S)-1-((2S,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)carbamoyl)-4-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 
clogPo/w (SwissADME)5.25
TPSA (SwissADME)237.41 Å2
No. of chiral centres3
No. of rotatable bonds23
No. of hydrogen bond acceptors12
No. of hydrogen bond donors6
Storagestable as powder at -20°C. NB making aliquots rather than freeze-thawing is recommended
Dissolutionsoluble in DMSO at 50 mM
Physical and Chemical Properties
Molecular weight999.12
Molecular formulaC51H57F3N8O9S
IUPAC nameN-(4'-((5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)carbamoyl)-4-morpholino-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 
clogPo/w (SwissADME)5.41
TPSA (SwissADME)243.40 Å2
No. of chiral centres3
No. of rotatable bonds23
No. of hydrogen bond acceptors12
No. of hydrogen bond donors6
Storagestable as powder at -20°C. NB making aliquots rather than freeze-thawing is recommended
Dissolutionsoluble in DMSO at 50 mM


Homer: CC1=C(C2=CC=C(CNC([C@@H]3C[C@@H](O)CN3C([C@H](C(C)(C)C)NC(CCCCNC(C4=CC=C(C5=CC=C(N6CCN(C)CC6)C(NC(C7=CNC(C=C7C(F)(F)F)=O)=O)=C5)C=C4)=O)=O)=O)=O)C=C2)SC=N1 

nc_VHL: CC1=C(C2=CC=C(CNC([C@@H]3C[C@H](O)CN3C([C@H](C(C)(C)C)NC(CCCCNC(C4=CC=C(C5=CC=C(N6CCN(C)CC6)C(NC(C7=CNC(C=C7C(F)(F)F)=O)=O)=C5)C=C4)=O)=O)=O)=O)C=C2)SC=N1 

nc_WDR5: CC1=C(C2=CC=C(CNC([C@@H]3C[C@@H](O)CN3C([C@H](C(C)(C)C)NC(CCCCNC(C4=CC=C(C5=CC=C(N6CCOCC6)C(NC(C7=CNC(C=C7C(F)(F)F)=O)=O)=C5)C=C4)=O)=O)=O)=O)C=C2)SC=N1 


Homer: InChI=1S/C52H60F3N9O7S/c1-31-45(72-30-59-31)34-11-9-32(10-12-34)27-58-49(70)42-25-37(65)29-64(42)50(71)46(51(2,3)4)61-43(66)8-6-7-19-56-47(68)35-15-13-33(14-16-35)36-17-18-41(63-22-20-62(5)21-23-63)40(24-36)60-48(69)38-28-57-44(67)26-39(38)52(53,54)55/h9-18,24,26,28,30,37,42,46,65H,6-8,19-23,25,27,29H2,1-5H3,(H,56,68)(H,57,67)(H,58,70)(H,60,69)(H,61,66)/t37-,42+,46-/m1/s1 

nc_VHL: InChI=1S/C52H60F3N9O7S/c1-31-45(72-30-59-31)34-11-9-32(10-12-34)27-58-49(70)42-25-37(65)29-64(42)50(71)46(51(2,3)4)61-43(66)8-6-7-19-56-47(68)35-15-13-33(14-16-35)36-17-18-41(63-22-20-62(5)21-23-63)40(24-36)60-48(69)38-28-57-44(67)26-39(38)52(53,54)55/h9-18,24,26,28,30,37,42,46,65H,6-8,19-23,25,27,29H2,1-5H3,(H,56,68)(H,57,67)(H,58,70)(H,60,69)(H,61,66)/t37-,42-,46+/m0/s1 

nc_WDR5: InChI=1S/C51H57F3N8O8S/c1-30-44(71-29-58-30)33-10-8-31(9-11-33)26-57-48(68)41-24-36(63)28-62(41)49(69)45(50(2,3)4)60-42(64)7-5-6-18-55-46(66)34-14-12-32(13-15-34)35-16-17-40(61-19-21-70-22-20-61)39(23-35)59-47(67)37-27-56-43(65)25-38(37)51(52,53)54/h8-17,23,25,27,29,36,41,45,63H,5-7,18-22,24,26,28H2,1-4H3,(H,55,66)(H,56,65)(H,57,68)(H,59,67)(H,60,64)/t36-,41+,45-/m1/s1 





selectivity profile
Quantitative Proteomics revealed that only WDR5 is significally and substantially depleted by Homer treatment. 
Homer binds potently to WDR5 as determined by ITC. 
in vitro potency
cell based assay data

Homer is cell permeable and degrades WDR5 in MV4-11 cells. The control compounds nc_WDR5 and nc_VHL are not active. 

NanoBRET data of Homer in HEX293 cells show Homer is cell permeable. 

(up) HiBiT assay curves from Homer (black) and both negative controls (red) as well as from parent WDR5 compound (blue) show that Homer degrades WDR5 in MV4-11 cells after 24 h. The most effective degradation (58% WDR5 depletion) is observed at 1 µM. (down) WesternBlots validate HiBiT data and show degradation of WDR5 by Homer treatment in MV4-11 cells after 24 h. 

Homer decreases WDR5 protein stability as shown in the Cycloheximide chase assay. 

Rescue experiments show that WDR5 depletion requires binding of Homer. WDR5 levels can be restored by excess of WDR5 ligand. 

qPCR shows that Homer does not affect WDR5 transcription.


[1] Wu, Shu, “MLL1/WDR5 complex in leukemogenesis and epigenetic regulation”, Chin. J. Cancer 2011, 30(4), 240-246.
[2] Jiang, “The complex activities of the SET1/ MLL complex core subunits in development and disease“, BBA – Gene Regulatory Mechanisms 2020, 1863, 194560.
[3] Thomas et al., “Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC”, Mol. Cell 2015, 58, 440-452.
[4] Grebien et al., “Pharmacological targeting of the Wdr5-MLL interaction in C/EBPa N-terminal leukemia”, Nat Chem Biol. 2015, 11, 571.
[5] Getlik et al., “Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)”, J Med Chem. 2016, 59, 2478.
[6] Dölle, Adhikari et al., “Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders”, J Med Chem. 2021, May 13. doi: 10.1021/acs.jmedchem.1c00146. Epub ahead of print. PMID: 33980013.
[7] A.C. Wallace, R.A. Laskowski, J.M. Thornton, “LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions”, Protein Eng. 8, 1995, 127-134.

pk properties
co-crystal structures


Left panel: Quaternary complex of WDR5:VHL:ElonginB:ElonginC:Homer bound to chemical probe PROTAC Homer in surface representation.

Right panel: Surface slice with focus on the binding pocket of WDR5 and VHL. Homer is shown in stick representation

Observed electron density of Homer countered at 1 sigma.

Left panel: Contact surface area between WDR5 (wheat) and VHL (green) in surface representation

Right panel: Close up on the detailed interaction between WDR5 and VHL in cartoon/stick representation. The orientation is the same as in the left Panel.

WDR5 (D)       

Detailed interaction between Homer and VHL:WDR5. The figure was created with LIGPLOT [7]

synthetic schemes
materials and methods