1.6.2 MLL-Menin Disruptors
Another druggable interaction is the MLL-menin one. The thienopyrimidine-based
compound MI-1 (49, Fig. 5) was the first small molecule to be identified as antagonist
of menin-MLL1 interaction (K D : 1.9 μM). Compound 49 was selected from a library
of 49,000 compounds through a fluorescent polarization-based screening. Following
structural optimizations on compound 49 yielded in order MI-2 (50) and MI-3 (51)
and MI-2-2 (52) (IC 50 of 446, 648, and 46 nM, respectively) (Fig. 5). In 2015, MI-463
(53) and MI-503 (54) (Fig. 5) were developed as orally bioavailable analogues of
compound 52 and proved to be effective in xenografted leukemia models
[100]. Starting from a linear octapeptide (MLL1 residues 6–13; RWRFPARP),
Zhou et al. developed macrocyclic peptidomimetic antagonists of the menin-MLL
interaction. Among them MCP-1 (55, Fig. 5) was the most efficient (K i : 4.7 nM),
being >600 times more potent than the acyclic analogue and 15 times more potent
than the initial linear hit [101]. Displaying a reduced molecular weight and peptidic
features compared to the original linear peptide, compound 55 is a promising starting
point for the development of cell-permeable menin-MLL disruptors. FP-based
screening of a 288,000-compound library, followed by hit optimization, resulted in
the identification of MIV-6R (56) (IC 50 : 56 nM), able to inhibit proliferation and
induce differentiation in different leukemia cell lines expressing MLL fusion
proteins [102].
1.7 The H3K4 Histone Methyltransferase SETD7
SETD7 (also known as SET9, SET7/9, or KMT7) was one of the first lysine
methyltransferases to be reported, and it was originally described as H3K4 monomethyltransferase [103]. SETD7 can be localized both in the cytoplasm and in the
nucleus, and its localization is regulated in an unusual way involving also other
cellular factors. Even if SETD7 displays a robust activity on H3K4 N-terminal
peptides in vitro, a little or null activity is observed on H3 substrate. Accordingly,
SETD7 knockdown or depletion does not affect the H3K4me levels in living cells
[103]. In time, a number of different studies highlighted the role of SETD7 as
modulator of various transcriptional regulators [103]. SETD7 is also involved in
the regulation of DNMT1 stability [103], DNA repair, cell differentiation, and cellcycle control. The number and the variety of its substrates place SETD7 as player in
several molecular pathways involved in cancer, metabolism (e.g., diabetes), inflammation, and viral infections (e.g., HIV, HCV infections) [103] (Fig. 6).
In 2014, the first SETD7 inhibitor, (R)-PFI-2 (57, Fig. 6), was reported as the result
of an HTS screening on a library of 150,000 compounds followed by lead optimization [104]. Compound 57 proved to be highly potent (IC 50 2.0 Æ 0.2 nM and
Morrison K i 0.33 Æ 0.04 nM) and selective for SETD7 over a panel of 18 MTs and
134 GPCRs, ion channels, and other enzyme targets. Interestingly, its enantiomer (S)140
G. Stazi et al.
Another druggable interaction is the MLL-menin one. The thienopyrimidine-based
compound MI-1 (49, Fig. 5) was the first small molecule to be identified as antagonist
of menin-MLL1 interaction (K D : 1.9 μM). Compound 49 was selected from a library
of 49,000 compounds through a fluorescent polarization-based screening. Following
structural optimizations on compound 49 yielded in order MI-2 (50) and MI-3 (51)
and MI-2-2 (52) (IC 50 of 446, 648, and 46 nM, respectively) (Fig. 5). In 2015, MI-463
(53) and MI-503 (54) (Fig. 5) were developed as orally bioavailable analogues of
compound 52 and proved to be effective in xenografted leukemia models
[100]. Starting from a linear octapeptide (MLL1 residues 6–13; RWRFPARP),
Zhou et al. developed macrocyclic peptidomimetic antagonists of the menin-MLL
interaction. Among them MCP-1 (55, Fig. 5) was the most efficient (K i : 4.7 nM),
being >600 times more potent than the acyclic analogue and 15 times more potent
than the initial linear hit [101]. Displaying a reduced molecular weight and peptidic
features compared to the original linear peptide, compound 55 is a promising starting
point for the development of cell-permeable menin-MLL disruptors. FP-based
screening of a 288,000-compound library, followed by hit optimization, resulted in
the identification of MIV-6R (56) (IC 50 : 56 nM), able to inhibit proliferation and
induce differentiation in different leukemia cell lines expressing MLL fusion
proteins [102].
1.7 The H3K4 Histone Methyltransferase SETD7
SETD7 (also known as SET9, SET7/9, or KMT7) was one of the first lysine
methyltransferases to be reported, and it was originally described as H3K4 monomethyltransferase [103]. SETD7 can be localized both in the cytoplasm and in the
nucleus, and its localization is regulated in an unusual way involving also other
cellular factors. Even if SETD7 displays a robust activity on H3K4 N-terminal
peptides in vitro, a little or null activity is observed on H3 substrate. Accordingly,
SETD7 knockdown or depletion does not affect the H3K4me levels in living cells
[103]. In time, a number of different studies highlighted the role of SETD7 as
modulator of various transcriptional regulators [103]. SETD7 is also involved in
the regulation of DNMT1 stability [103], DNA repair, cell differentiation, and cellcycle control. The number and the variety of its substrates place SETD7 as player in
several molecular pathways involved in cancer, metabolism (e.g., diabetes), inflammation, and viral infections (e.g., HIV, HCV infections) [103] (Fig. 6).
In 2014, the first SETD7 inhibitor, (R)-PFI-2 (57, Fig. 6), was reported as the result
of an HTS screening on a library of 150,000 compounds followed by lead optimization [104]. Compound 57 proved to be highly potent (IC 50 2.0 Æ 0.2 nM and
Morrison K i 0.33 Æ 0.04 nM) and selective for SETD7 over a panel of 18 MTs and
134 GPCRs, ion channels, and other enzyme targets. Interestingly, its enantiomer (S)140
G. Stazi et al.