activity by allosteric effects [45]. MET activation has been reported to promote
tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies, including against anti-EGFR cancer agents [46].
To date, there is no selective MET inhibitor that is FDA-approved. Crizotinib
(Xalkori) was originally tested in MET deregulated lung cancer patients but obtained
its primary registration as ALK inhibitor in ALK translocation-positive NSCLC
[47]. Several orally bioavailable MET tyrosine kinase inhibitors are currently in
advanced clinical trials [48]. We will describe thereafter the discovery process which
allowed the identification of SAR125844, an exquisite selective MET inhibitor
investigated in phase II clinical trials for MET-amplified NSCLC patients (https://
clinicaltrials.gov/ct2/show/NCT01391533).
From a two-step screen of a limited set of in house compounds, a hit (cpd 6,
Scheme 2) was identified with low nanomolar potency against wild-type (WT) MET
(IC 50 ¼ 10 nM), but this molecule also exhibited a marked affinity for tubulin, a
major constituent of the cytoskeleton involved in DNA segregation, leading then to
off-target cytotoxicity in non-MET-dependent tumor cell lines [49, 50].
Compound 6 displayed otherwise no activity (IC 50 > 10 μM) against a panel of
kinases tested, in particular CDK9 a key player in cell cycle regulation and gene
transcription [51]. This potent and selective MET inhibitor, obtained in a rather
straightforward manner by compound collection screen, exhibited the
A
B
H1094Y
L1195V
Y*1230H
Y*1235D
M1250T
D 1222- F 1223- G 1224
Glu1127
N-lobe Lys1110
GK Leu1157
H 1202- R 1203- D 1204
Cat Arg1208
Pro 1158- Tyr 1159- Met 1160
Hinge
Phosphorylation
Tyr1234&1235
MET
active
site
Val1201
Phe1200
Gly1163
Met1211
Ala1221
GRL
Arg1086
C
Met1131
Leu1225
Leu1155
GRL
Phe1089
Leu1142
Val1156
Asp1164
C
Fig. 7 (a, b) KMM of MET
N
N
H
N
H
O
O
S
N
N
N
N
F
S
N
N
H
O
O
S
N
N
N
N
F
N
N
N
N
S
F
N
S
N
H
N
H
O
N
O
6
7
11 (SAR125844)
Scheme 2 From hit to candidate
104
L. Schio and H. Minoux
tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies, including against anti-EGFR cancer agents [46].
To date, there is no selective MET inhibitor that is FDA-approved. Crizotinib
(Xalkori) was originally tested in MET deregulated lung cancer patients but obtained
its primary registration as ALK inhibitor in ALK translocation-positive NSCLC
[47]. Several orally bioavailable MET tyrosine kinase inhibitors are currently in
advanced clinical trials [48]. We will describe thereafter the discovery process which
allowed the identification of SAR125844, an exquisite selective MET inhibitor
investigated in phase II clinical trials for MET-amplified NSCLC patients (https://
clinicaltrials.gov/ct2/show/NCT01391533).
From a two-step screen of a limited set of in house compounds, a hit (cpd 6,
Scheme 2) was identified with low nanomolar potency against wild-type (WT) MET
(IC 50 ¼ 10 nM), but this molecule also exhibited a marked affinity for tubulin, a
major constituent of the cytoskeleton involved in DNA segregation, leading then to
off-target cytotoxicity in non-MET-dependent tumor cell lines [49, 50].
Compound 6 displayed otherwise no activity (IC 50 > 10 μM) against a panel of
kinases tested, in particular CDK9 a key player in cell cycle regulation and gene
transcription [51]. This potent and selective MET inhibitor, obtained in a rather
straightforward manner by compound collection screen, exhibited the
A
B
H1094Y
L1195V
Y*1230H
Y*1235D
M1250T
D 1222- F 1223- G 1224
Glu1127
N-lobe Lys1110
GK Leu1157
H 1202- R 1203- D 1204
Cat Arg1208
Pro 1158- Tyr 1159- Met 1160
Hinge
Phosphorylation
Tyr1234&1235
MET
active
site
Val1201
Phe1200
Gly1163
Met1211
Ala1221
GRL
Arg1086
C
Met1131
Leu1225
Leu1155
GRL
Phe1089
Leu1142
Val1156
Asp1164
C
Fig. 7 (a, b) KMM of MET
N
N
H
N
H
O
O
S
N
N
N
N
F
S
N
N
H
O
O
S
N
N
N
N
F
N
N
N
N
S
F
N
S
N
H
N
H
O
N
O
6
7
11 (SAR125844)
Scheme 2 From hit to candidate
104
L. Schio and H. Minoux