Table 16.1.

Inhibitors targeting MDM2-MDMX loop discovered by different strategies

Small molecule	Status	ID	Scaffold	Discover methods	Ki or IC50	In vivo test	Reference
M2-p53 interactiona	Preclinical	Nutlin-3c	Imidazolines	HTS, SPR assay	~0.1 µM	Retinoblastoma	[44]
	Phase I	RG7112 (RO5045337)			18 nM	Advanced malignancies, except leukemia	[100]
M2-p53 interaction	Preclinical	MI63, MI-219	Spirooxindoles	Structure-based design	~1–50 nM	SJSA-1 xenograft	[94]
	Phase I	MI-773 (SAR405838)				Advanced cancer	[63]
M2-p53 interaction		NSC333003c	Benzothiazoles	Virtual screening	~20 µM		[150]
M2-p53 interaction	Preclinical	TPD222669	Benzodiazepines	HTS ThermoFlor	0.08 µM	A3 7 5 xenograft	[151]
M2-p53 interaction	Preclinical	YH265	Pyrazoles	HCS, Biosensor	1.8 µM	NCI60 cancer cells	[83, 84] WO2011106650
M2-p53 interaction	Phase I	CGM097 (Novartis)			<50 nM	Selected advanced and refractory solid tumors	[63]
M2-p53 interaction	Phase I	MK-8242 (Merck)	Piperidines				[63]
M2-p53 interaction	Preclinical	PXN727 (Priaxon)	Isoquinoline-1-ones, pyrrolinones	Virtual screening	8 nM-1 µM	LNCaP xenograft	http://www.priaxon.com/content/_docs/docl264519272209.pdf
M2-p53 interaction			Tetra-substituted heteroaryls	Structure-based design	1 nM-50 µM		[63]
M2-p53 interaction		c	Substituted pyrazoles	Structure-based design	M2: ~0.02 µM; MX: ~10 µM
M2-p53 interaction		c	Indole-2-carboxylic acids	Structure-based design	130–400 nM
M2-p53 interaction			Indolinones	Structure-based design	1.2nM-3.7nM
M2-p53 interaction			Piperidines	Structure-based design	0.02–0.27 µM
M2-p53 interaction	Preclinical	AM-8553	Piperidinones	Structure-based design	150 nM	SJSA xenograft	[96]
M2-p53 interaction	Preclinical		Pyrrolidone	Virtual screening, FP assay	0.26 µM	A549 xenograft	[152]
MX-p53 interactionb	Preclinical	SJ-172550c SJ000558295	Imidazolines	HTS,FP assay HTS.FP	~1 µM M2:9.1 µM; MX: ~9.0 µM	Retinoblastoma cells	[59] [63]
	Preclinical	SJ000558304		HTS.FP	M2:>150nM; MX: ~2 µM
MX-p53 interaction		XI-006	Benzofuroxans	HCS, luciferase reporter assay		MCF-7 cells	[60]
Dual inhibitor	Preclinical	RO-2443, RO-5963c	Indolyl Hydantoins	HTS,TR-FRET Assay	M2 and MX: <50 nM	MCF7, HCT, RKO cells	[61]
Dual inhibitor?	Phase I	RO5503781	Indolyl Hydantoins?			Soft tissue sarcoma; leukemia	[103] NCT01462175
Dual inhibitor		Novartis	Isoquinolinones	TR-FRET	M2: 0.8 nM; MX: 1.36 µM		[63]
Dual inhibitor			Imidazoles, imidazolines	Virtual screening, MCR	M2: 15 nM; MX: 1 µM	HCT116 cells	[65]
M E3 ligase inhibitor	Preclinical	MEL23, MEL24		Cell-based assay	7.5 µM, 9.2 µM	U20S, HCT116 et al.	[49]
M2 E3 ligase inhibitor	Preclinical	MPD		Cell-based assay	1–50 µM		[48]
M2 E3 ligase inhibitor	Preclinical	HLI98		Cell-based assay	−50 µM		[47]
M2-proteasome interaction	Phase I	JNJ-26854165	Cyclic alkyl amines	Cell-based assay	>0.5 µM	Advanced stage solid tumors	[45] WO2008132175
p53 N terminal binder?	Preclinical	RITA		Cell-based assay			[153, 154]
Peptidic compound
Dual inhibitor	Preclinical	SAH-p53-8		Phage library	M2: 55 nM; MX: 2.3 nM	Cutaneous melanoma	[87,88, 114]
Peptidic compound
Dual inhibitor		β53–16		Phage library	M2: ~50 nM; MX: >100 nM		[155]
Peptide
Dual inhibitor		(D)PMI-gammac	DWWPLAFEALLR	Mirror image phage display	M2 and MX: <50 nM	U87 xenograft	[79]
Peptide
Dual inhibitor		PDIc	LTFRYWC1RQLS	Phage library	220 pM		[80]

^aM2 indicates MDM2

^bMX indicates MDMX

^c3D co-crystal structures are available via PDB protein data bank