A therapeutic patent overview of MDM2/X-targeted therapies (2014–2018)

Figures & data

Figure 1. Structure and in vitro activity of exemplary MDM2 inhibitors based on a 5 membered ring: cis-imidazoline scaffold. The IC₅₀ value for nutlin 3 was is from [21] and for RG-7112 from [24].

Table 1. MDM2/X antagonists with monocyclic core structures.

Core structure				Target
type of rings		the core	Assignee/patent No. (2014–2018)	MDM2	MDMX	Combination	Examples	Compounds in clinical trials
monocyclic	5-member	cis-imidazoline	Hoffmann-La Roche US 2014/0140988 A1 [82] US 2014/0148443 A1 [25] St. Jude Hospital WO 2015/184383 A1 [26]	Yes Yes Yes	– Yes Yes	Yes – –	(3) (4)	RG7112 (2)
		pyrrolidine	Roche US 2015/0157603 A1 [29] US 2017/0008904 A1 [31] WO 2016/188935 A1 [83]	Yes Yes Yes	– – –	Yes Yes Yes	(6)	RG7388 (5)
		3-pyrrolin-2-one	Adamed Sp. z o.o. WO 2015/004610 A1 [32]	Yes	Yes	–	(7) (20)	–
	6-member	piperidinone (X = C) morpholinone (X = O)	Amgen Inc. US 2014/0243372 A1 [33] US 2014/0364455 A1 [36] WO 2015/070224 A2 [37] WO 2014/130470 A1 [34] WO 2014/151863 A1 [35]	Yes Yes Yes Yes Yes	– – – – –	– – Yes – –	(9) (10) (11)	AMG-232 (8)

Figure 2. Structure and in vitro activity of exemplary MDM2 inhibitors based on 5 membered ring: pyrrolidine and pyrrole scaffolds. The IC₅₀ value for RG7388 was is from [28].

Figure 3. Structure and in vitro activity of exemplary MDM2 inhibitors based on 6 membered ring: piperidinone and morpholinone scaffolds. The IC₅₀ value for AMG-232 was is from [94].

Table 2. MDM2/X antagonists with bicyclic and multicyclic core structures.

Core structure				Target
type of rings		the core	Assignee/patent No. (2014–2018)	MDM2	MDMX	Combination	Examples	Compounds in clinical trials
bicyclic	6 + 5-member	pyrrolopyrimidines	Merck Sharp & Dohme Corp. WO 2014/100071 A2 [41]	Yes	–	–	(12)	–
		purine	Merck Sharp & Dohme Corp. WO 2014/123882 A1 [43] WO/2014/120748 A1 [42]	Yes Yes	– –	– –	(13) (14)	–
		isoindolin-1-one	Astex Therapeutics Ltd. WO 2017/055859 A1 [44] WO 2017/055860 A1 [45]	Yes Yes	– –	– –	(15) (16)	–
	5 + 5-member	pyrrolidonopyrazole	The Second Military Medical University WO/2014/134968 A1 [46]	Yes	–	–	(17)	–
		pyrrolidonoimidazole	Novartis Ag WO 2015/084804 A1 [47]	Yes	–	Yes		HDM201 (18)
	6 + 6-member	dihydro-isoquinolin-3-one	Novartis Ag WO 2015/084804 A1 [47] WO 2016/035023 A1 [85] WO 2017/037586 A1 [86] WO 2017/037579 A1 [87] WO 2017/029588 A2 [88] WO 2018/092064 A1 [89]	Yes Yes Yes Yes Yes Yes	– – – – – –	Yes Yes Yes Yes Yes Yes		CGM097 (19)
multicyclic		acridine	Mirx Pharmaceuticals US 2017/0022166 A1 [52]	–	Yes	–	(21)	–
		beta-carboline	Texas Tech WO 2016/049453 A1 [81] US 2017/0283413 A1 [40]	Yes Yes	– –	– –		–

Figure 4. Structure and in vitro activity of exemplary MDM2 inhibitors based on bicyclic core (5 + 6): purine, pyrrolopyrimdine, isoindolinone scaffolds.

Figure 5. Structure and in vitro activity of exemplary MDM2 inhibitors based on bicyclic core (5 + 5 and 6 + 6): pyrrolidonopyrazole, pyrrolidonoimidazole, dihydro-isoquinolin-3-one scaffolds. The IC₅₀ value for CGM097 was is from [48].

Figure 6. Structure and in vitro activity of exemplary MDMX inhibitors.

Figure 7. Structure and in vitro activity of exemplary MDM2 inhibitors based on spiro-oxindoles connected with 5-membered ring: pyrrolidine and pyrrolinone. The IC₅₀ value for MI-77301 was is from [96] and for MI-1061 from [59].

Figure 8. Structure and in vitro activity of exemplary MDM2 inhibitors based on spiro-oxindoles connected with multiple rings.

Table 3. MDM2/X antagonists based on spiro-oxindole core structures.

Core structure				Target
type of rings		the core	Assignee/patent No. (2014–2018)	MDM2	MDMX	Combination	Examples	Compounds in clinical trials
spiro-oxindole	5-member	pyrrolidine	Sanofi EP 2 752 191 A1 [56] Daiichi Sankyo WO 2018/074387 A1 [91] University of Michigan WO 2015/161032 A1 [57] US 2015/0299211 A1 [58] Hudson Biopharma Inc. US 2015/0322076 A1 [55]	Yes Yes Yes Yes	– – – –	Yes Yes – –	(25) (23)	MI-77301 (22) APG-115 DS-3032b
		3-pyrrolin-2-one	Adamed Sp. z o.o. WO 2015/189799 A1 [60]	Yes	–	–	(26)	–
	bicyclic (5 + 5 member)	octahydropyrrolopyrrol	Adamed Sp. z o.o. WO 2015/189799 A1 [60] Boehringer Ingelheim International Gmbh WO 2015/155332 A1 [62]	Yes Yes	– –	– –	(27) (29)	–
		hexahydropyrrolopyrrolone	Boehringer Ingelheim International Gmbh US 2015/0291611 A1 [61] WO 2016/001376 A1 [63]	Yes Yes	– –	– –	(30)	–
		pyrrolothiazole	King Saud University US 9822128 B1 [54]	Yes	–	–	(28)	–
	multicyclic		Boehringer Ingelheim International Gmbh WO 2016/026937 A1 [64]	Yes	–	–	(31)	–
		X = N; Y, Z = C Y = N; X, Z = C Z = N; X, Y = C	Boehringer Ingelheim International Gmbh WO 2017/060431 A1 [65]	Yes	–	–	(32)	–

Figure 9. Structure and activity of exemplary compounds utilizing PROTAC technology and MDM2 E3 ligase activity.

Figure 10. Exemplary peptide inhibitors of MDM2/X protein.

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