Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant

Article abstract of DOI:10.1016/j.bmcl.2011.04.060

Ponatinib (AP24534) was previously identified as a pan-BCR-ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponatinib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in this series displayed excellent in vitro potency against both native BCR-ABL and the T315I mutant. Notably, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven CML.

Full text of DOI:10.1016/j.bmcl.2011.04.060

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3743–3748
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent
inhibitors of BCR–ABL including the T315I gatekeeper mutant
⇑
Mathew Thomas , Wei-Sheng Huang, David Wen, Xiaotian Zhu, Yihan Wang, Chester A. Metcalf,
Shuangying Liu, Ingrid Chen, Jan Romero, Dong Zou, Raji Sundaramoorthi, Feng Li, Jiwei Qi, Lisi Cai,
Tianjun Zhou, Lois Commodore, Qihong Xu, Jeff Keats, Frank Wang, Scott Wardwell, Yaoyu Ning,
Joseph T. Snodgrass, Marc I. Broudy, Karin Russian, John Iuliucci, Victor M. Rivera, Tomi K. Sawyer,
David C. Dalgarno, Tim Clackson, William C. Shakespeare
ARIAD Pharmaceuticals Inc., 26 Lansdowne Street, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Ponatinib (AP24534) was previously identified as a pan-BCR–ABL inhibitor that potently inhibits the
T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory
or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alter-
nate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponati-
nib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in
this series displayed excellent in vitro potency against both native BCR–ABL and the T315I mutant. Nota-
bly, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven
CML.
Received 16 March 2011
Accepted 14 April 2011
Available online 22 April 2011
Keywords:
BCR–ABL inhibitors
Gatekeeper mutant
Chronic myeloid leukemia
Ponatinib
Ó 2011 Elsevier Ltd. All rights reserved.
Monocycles
Imatinib (Gleevec, ST1571), a small molecule BCR–ABL inhibitor
is a proven and effective frontline therapy for the treatment of
chronic myeloid leukemia (CML).1 Despite the impressive clinical
success of imatinib in treating early phase CML, acquired resistance
has surfaced as an important limitation of the drug. Such resistance
is often associated with the emergence of point mutations in the
ABL kinase domain that impede inhibitor binding.2 To address
these mutations, two second generation inhibitors nilotinib
(Tasigna, AMN107) and dasatinib (Sprycel, BMS-354825) have
been developed.3 Despite the effectiveness of these newer agents
which successfully target most imatinib failures, pockets of
resistance still remain, and neither compound inhibits the T315I
mutant, which constitutes ꢀ15–20% of all clinically observed
mutations.4 To identify next-generation inhibitors capable of
overcoming resistance, we focused on compounds which target
not only BCR–ABLT315I but also the native (unmutated) form of
the protein, and all other known resistant mutations. Such a
pan-BCR–ABL inhibitor should exert high levels of disease control
in patients resistant or refractory to current agents, and have the
potential to thwart all resistance if used early in disease
treatment.
As a part of our ongoing program targeting DFG-out based ABL
inhibitors, we have previously described a series of purine based,
ATP competitive dual Src/ABL inhibitors5 which displayed modest
cellular potency against BCR–ABLT315I
. Subsequent structure
guided optimization led to the discovery of ponatinib,6 a highly
potent and orally bioavailable pan-BCR–ABL inhibitor including
T315I. Ponatinib has advanced into clinical trials for the treatment
of CML patients with resistance to prior therapy. A full description
of the medicinal chemistry strategy leading to the discovery of this
compound has been described in a recent publication.7
To further probe ponatinib SAR, particularly in the hinge region,
efforts were undertaken to explore replacing the 6,5-fused imidaz-
opyridazine core with small subsets of potential five and six mem-
bered monocyclic hinge-binding moieties such as 7 and 8 tethered
to pendant toluanilides via an ethynyl linker (Fig. 1).8 Monocycles
capable of forming one or two hinge region H-bonds were in-
cluded, and the effects on potency, PK and kinase selectivity were
monitored relative to ponatinib. A recent report highlights a simi-
lar strategy where low nM inhibitors of BCR–ABLT315I exemplifying
both mono and bicyclic hinge-binding templates were disclosed.9
To guide our design efforts, we first conducted docking studies
to elucidate key molecular recognition elements between proto-
type inhibitor 8h and the ABLT315I kinase domain. The model was
built based on the recently published crystal structure of ponati-
nib6,10 in complex with ABLT315I (RCSB code: 3OY3).
⇑
Corresponding author.
E-mail address: Mathew.thomas@ariad.com (M. Thomas).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.060

3744
M. Thomas et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3743–3748
Figure 1. Evolution of hetero-monocyclic BCR–ABLT315I inhibitors from ponatinib (AP24534).
As shown in the docked model, 8h binds to ABLT315I through a
ability to make an additional hinge region H-bond while forfeiting
close van der Waals interactions with the P-loop.
DFG-out mode (Fig. 2). The monocyclic core of 8h forms two
H-bonds with the backbone of M318 in the kinase hinge region.
Additionally, three more hydrogen bond contacts arise between
the amide of the ligand and the backbone of D381 and the side
chain of E286, as well as between the backbone of I360 and the ba-
sic hydroxyethyl piperazine tail stretching into the solvent front. In
addition, extensive van der Waals molecular contacts are made
throughout the entire molecule, particularly around F382 of the
DFG motif. These include the contacts of F382 with the tolyl moi-
ety, the ethynyl linkage and the monocyclic core of 8h. The ethynyl
group of 8h makes favorable hydrophobic interactions with the
mutated gatekeeper isoluceine residue subjugating this highly
restricted structural requirement for this mutation. The N-methyl
substituent of the imidazole core also makes additional van der
Waals interactions with the hinge region compared with
ponatinib.10
Having determined the key structural features required for
optimal protein interaction, we prepared a series of five and six
membered monocyclic derivatives for testing in enzymatic and
cellular assays. Based on our previously described synthetic route
to this chemical class,7 we first introduced the acetylenic side
chain by subjecting commercially available hetero-aryl bromides
1a–f to standard Songashira coupling conditions followed by pro-
todesilylation to afford 2a–f in good yields (Scheme 1). Similarly,
the acetylenic azole precursors 5a–c, 5k and 5l required for com-
pounds 8a–c, 8k and 8l were all prepared in an analogous fashion
(Scheme 1).
For the remaining azole alkynyl derivatives 5d–f a slightly dif-
ferent strategy was adopted in order to install the necessary C2
amides. Commercially available 5-bromo N-methyl imidazole
was first converted into a common protected acetylenic derivative
3 via the process outlined above. Subsequent deprotonation with
n-butyllithium led to C-2 lithioimidazole intermediacy followed
by quenching with trimethyl isocyanate furnished the respective
primary amide precursor which on protodesilylation under basic
conditions provided 5d.11 In case of amides 4e and 4f, acetylenic
In contrast to ponatinib, the P-loop of ABLT315I adopts a more
open conformation in ABLT315I when bound with 8h making lim-
ited van der Waals interactions with the inhibitor. This is most
likely caused by the change of the 6,5-fused bicyclic core in ponati-
nib compared to the monocyclic core in 8h resulting in the loss of
edge-to-face aromatic interactions between Y253 located in the
P-loop and the hinge binding core of 8h. Overall, the model sug-
gests that 8h binds similar to ponatinib in ABLT315I but with the
precursor
3 was likewise treated with n-butyllithium and
quenched with dry ice to yield the corresponding acid derivative
which was further coupled with either methylamine or 2-amino-
ethanol produced the required amides. Consequent release of the
silyl group from the amide precursors under basic conditions pro-
vided terminal alkynes 5e and 5f in quantitative yields (Scheme 2).
Scheme 1. Reagents and conditions: (a) TMS acetylene, Pd(PPh3)4, CuI, DMF, 80 °C;
(b) K2CO3, MeOH–THF.
Figure 2. Model of inhibitor 8h bound to ABLT315I kinase.

M. Thomas et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3743–3748
3745
Scheme 2. Reagents and conditions: (a) TMS acetylene, Pd(PPh3)4, CuI, DMF, 80 °C; (b) n-BuLi, TMSNCO, THF À78 °C; (c) n-BuLi, CO2, THF À78 °C; (d) MeNH2 or 2-amino
ethanol, CDI, THF; (e) K2CO3, MeOH–THF.
Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, CuI, DMF, 80 °C.
As depicted in Scheme 3, the fully elaborated compounds were
then prepared individually by executing a second Sonagashira cou-
pling reaction between precursors 2a–f with the previously de-
scribed iodo benzamide 6a7 to furnish the corresponding target
compounds 7a–f. Similarly, compounds 8a–l were obtained via
the same route outlined for 7a–f using the appropriate substituted
iodobenzamides 6b–d, respectively.
Compounds were evaluated for their kinase inhibitory activity
against both native and mutant (T315I) ABL as previously de-
scribed.7 Cellular activity was assessed with Ba/F3 cells transfected

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M. Thomas et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3743–3748
Table 1
Structure–activity relationship for inhibitors 7 and 8 (IC50s in nM)
Compd
X
R1
R2
ABL kinasea
ABLT315I kinasea
BCR–ABL (Ba/F3)
BCR–ABLT315I (Ba/F3)
Parental (Ba/F3)
Ponatinib
CH3
CH3
CH3
CH3
CH3
CH3
8.6
40
1.2
4.1
3.1
2.2
2.5
2.6
8.8
45.5
65
9.6
13.4
18
1219
2038
2818
1787
1659
1021
7a
7b
7c
7d
7e
CH
N
CH
CH
CH
H
H
40.3
62.7
18
28.6
48.7
123
435
121
104
321
NHCOCH3
NHCOCH2CH3
CONH2
7f
N
CH3
49.7
457
195
519
607
HN
8a
8b
8c
8d
8e
8f
8g
8h
8i
NH
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH2OH
CH2CH2OH
CH2CH2OCH3
CH2CO2H
CH3
1000
129
72.6
3.6
17.4
55
3.6
17.2
4.8
3717
550
362
25
18
301
36
60.2
140
106
139
27
730
43
8.5
1.3
1.7
3.9
0.61
1.3
0.65
7.6
2.8
5738
709
69
7.6
4
6549
5647
1793
787
1583
1603
1320
3093
2378
10000
1269
97
NCH3
NCH3
NCH3
NCH3
NCH3
NCH3
NCH3
NCH3
NCH3
S
CONH2
CONHCH3
CONHCH2CH2OH
CONH2
CONHCH3
CONH2
CONH2
NH2
64
5.8
8.4
10.8
64
17.5
5.5
8j
8k
8l
4.3
29
12
S
NHCOCH3
CH3
0.67
a
All data in this study were obtained from in-house assays. In a different enzymatic assay conducted by Reaction Biology Corporation,12 the IC50s of ponatinib were
determined to be 0.37 (ABL) and 2.0 nM (ABLT315I), as previously reported.6
with native BCR–ABL or BCR–ABLT315I using inhibition of parental,
non-transfected Ba/F3 cells as a control (Table 1).
We focused initially on a discrete subset of azine scaffolds 7 that
could recapitulate the key hinge H-bond while conserving all ele-
ments of molecular recognition that contributed to the potency
of ponatinib including the tolyl moiety and the trifluoromethyl
phenyl group bearing the N-methyl piperazine moiety.
In general, comparison of prototype azines 7a and 7b versus
ponatinib revealed decreased ABLT315I kinase activity (3 and 10
fold, respectively) and 4–7 fold potency reduction in Ba/F3 cells
expressing BCR–ABLT315I. In part this may be attributed to the
inability of both inhibitors to form close van der Waals contacts
with the P-loop as seen with ponatinib.
Introduction of an acetamido group at position C2 yielded com-
pounds 7c and 7d both with significantly increased enzymatic and
cellular potencies relative to the parent 7a (Table 1). The potency
gain presumably arises from the additional hydrogen bond be-
tween the exocyclic NH of the template and M318 in the kinase
hinge region notwithstanding the aforementioned loss of P-loop
interactions. Despite the increased potency, previous experience
with similar molecules targeting alternate kinases suggested they
would be rapidly metabolized in vivo and so they were no longer
pursued.
markedly shifted by 29 fold (18–513 nM) suggesting that 7e was
highly protein bound. Next we capped the C2 exocyclic primary
amine with a cyclopropyl group yielding 7f. Although we have pre-
viously used this functionality to identify compounds with good
oral bioavailability and attenuated protein binding in an alternate
series5 surprisingly, this modification markedly reduced both
kinase and cellular activities >10 fold (IC50 of 457 and 519 nM,
respectively) relative to both ponatinib and 7c–e.
In parallel to our investigation of azine derivatives we also ex-
plored a series of azole moieties 8 and evaluated them for activity.
Compared to ponatinib, the imidazole prototype inhibitor 8a was
essentially inactive in both kinase and cellular assays, likely due
to significantly decreased hydrophobic contact between the inhib-
itor core and the protein. The N-methyl imidazole analog 8b im-
proved potency relative to 8a suggesting that the N-1 methyl
substituent on the imidazole ring occupies a similar position to
N-5 of the ponatinib bicyclic core. Interestingly, the dimethyl ana-
log 8c exhibited two fold increased kinase activity relative to 8b
but was 10 fold more active in cells against BCR–ABLT315I
.
Analogously to the approach with azine analogues, carboxy-
amide substituents at C2 were installed to serve as acyclic surro-
gates for a purine template whereby the NH2 of the carboxy
amide is expected to be equivalent to the exocyclic 6-amino
group of the adenine core, preserving the required paired H-
bonds to the kinase hinge region.5 Inhibitor 8d was synthesized,
tested and indeed, displayed comparable potency to ponatinib
in the ABLT315I kinase and BCR–ABLT315I mutant Ba/F3 cell assays
(IC50s of 25 and 7.6 nM, respectively). Encouraged by these
results, further SAR around this series was explored. The simple
N-methylated carboxamide analog 8e, also exhibited similar
Given the importance of the paired hinge region H-bonds, we
sought alternative ways to maintain these interactions but with in-
creased metabolic stability. Thus we tested inhibitor 7e bearing a
stable primary carboxamide. Compound 7e exhibited similar
in vitro potency (Table 1) relative to 7c and 7d, however, when
tested in the presence of physiological concentrations of human
serum albumin,5 cellular potency against BCR–ABLT315I was

M. Thomas et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3743–3748
3747
Table 2
Pharmacokinetic profile for selected compounds
Rata
Mouseb
po
iv
po
Compd
Cmax (ng/mL)
t1/2 (h)
AUC (h/ng/mL)
Vd (L/kg)
CI (L/h/kg)
Cmax (ng/mL)
t1/2 (h)
AUC (h/ng/mL)
F (%)
C6h (ng/mL)
7b
8d
8g
8h
822
627
598
200
6.2
7.0
3.5
5.6
5308
5445
2320
970
8.5
9.3
11
0.94
0.92
2.15
1.03
900
258
61.4
344
10
13,559
4144
962
85.0
25.3
14.0
45
771
358
333
8.0
6.3
10
8.2
6586
1148
a
Dosed iv in rats @ 5 mg/kg, po dosed @ 15 mg/kg.
Dosed po in mice @ 30 mg/kg.
b
kinase and cellular activities. However, further attempts to in-
crease potency through incorporation of more hydrophilic
a
amide 8f resulted in reduced kinase and cellular activity relative
to 8d and 8e.
Next we briefly explored piperazine ring SAR, both as a means
to increase potency and modify the ADME properties of this series.
For this purpose, we simultaneously prepared matched sets of both
8d and 8e by further substituting the basic N-methyl group with
more hydrophilic side chains, yielding 8g and 8h. When tested,
both compounds exhibited similar potencies relative to their par-
ent compounds 8d and 8e. Since, inhibitor 8g was slightly more
active it was further modified to ether 8i and acid 8j, however,
these analogues offered no significant advantage relative to 8g or
were less potent.
Lastly, we also explored alternate azole moieties such as amino-
thiazole derivatives 8k and 8l as potential bioisosteres of pyrimi-
dine inhibitor 7f. Both analogues retained potency against the
native and mutated forms of BCR–ABL with the caveat that 8l po-
tently inhibited the Ba/F3 parental cell line with an IC50 of 97 nM,
suggesting a loss of selectivity.
Figure 3. Comparative in vivo efficacy in a Ba/F3 BCR–ABLT315I survival model
following 19 daily oral doses (10 mg/kg, error bars represent SD).
To probe the ADME properties of this series, we evaluated sev-
eral potent compounds in a rat pharmacokinetic model in parallel
with the in vitro assays. In general, potent compounds from both
series displayed good clearance properties and modest to excellent
oral bioavailability. Among those analogues, 7b exhibited the high-
est oral exposure and longest half-life (t1/2) (Table 2). The remain-
ing inhibitors, ranked as follows: 8h > 8d > 8g.
In preparation for efficacy studies, mouse PK data were also
determined at a single 6 h time point. Notably, 8h demonstrated
the highest plasma concentration when dosed orally at 30 mg/kg
(Table 2).
Several inhibitors possessing desirable in vitro potency and
with favorable pharmacokinetic profiles were further evaluated
for their anti-tumor activity in an aggressive mouse model of
CML driven by the T315I mutation.6 In this survival model, mice
were injected intravenously with Ba/F3 BCR–ABLT315I cells. After
three days, the animals were dosed orally, once-daily with inhibi-
tors at 10 mg/kg for 19 consecutive days. The level of increased
overall survival of treated mice relative to untreated control was
used to assess efficacy. The median survival time for vehicle-
treated mice was 15 days. Among all the inhibitors tested, 8h
demonstrated the greatest increased overall survival (Fig. 3) and
was comparable to the ponatinib control.
In a second study, 8h exhibited excellent dose-dependency and
significantly prolonged median survival to 37 days at the highest
dose tested (30 mg/kg) representing 130% increase in overall
survival relative to vehicle control group with no signs of overt
toxicity (Fig. 4). This potency is similar to that previously observed
with ponatinib.6
Figure 4. In vivo efficacy of 8h in a Ba/F3 BCR–ABLT315I survival model following 19
daily oral doses.
viously described.6 Similar to ponatinib, the incorporation of the
alkyne moiety adjacent to the gatekeeper residue imparts a degree
of kinase promiscuity, despite the additional hinge region H-bond
in the monocyclic template (Table 3). 8h inhibited the ephrin,
FGFR, FLT, PDGFR and Src family of kinases with IC50s within 10
fold of that for the ABL T315I mutant. Notably, all of these kinases
contain small to medium size gatekeeper residues that are more
easily accommodated by the linear acetylene linkage. Like ponati-
nib, 8h was completely inactive against Aurora A, CDK2 and the
insulin receptor tyrosine kinase.
To assess the kinase selectivity profile and examine the effects
of an additional hinge-region H-bond on specificity, 8h was
screened against a broad kinase panel using enzyme assays as pre-

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M. Thomas et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3743–3748
Table 3
References and notes
Kinase inhibition profile of 8h against selected kinases
1. (a) Druker, B. J.; Guilhot, F.; O’Brien, S. G.; Gathmann, I.; Kantarjian, H.;
Kinase
IC50 (nM)
Kinase
IC50 (nM)
Gattermann, N.; Deininger, M. W.; Silver, R. T.; Goldman, J. M.; Stone, R.
M.; Cervantes, F.; Hochhaus, A.; Powell, B. L.; Gabrilove, J. L.; Rousselot, P.;
Reiffers, J.; Cornelissen, J. J.; Hughes, T.; Agis, H.; Fischer, T.; Verhoef, G.;
Shepherd, J.; Saglio, G.; Gratwohl, A.; Nielson, J. L.; Radich, J. P.;
Simonsson, B.; Taylor, K.; Baccarani, M.; So, C.; Letvak, L.; Larson, R. A.
N. Engl. J. Med. 2006, 355, 2408; (b) Druker, B. J.; Tamura, S.; Buchdunger,
E.; Ohno, S.; Segal, G. M.; Fanning, S.; Zimmermann, J.; Lydon, N. B. Nat.
Med. 1996, 2, 561; (c) Capdeville, R.; Buchdunger, E.; Zimmermann, J.;
Matter, A. Nat. Rev. Drug Disc. 2002, 1, 493.
ABL
ABL(T315I)
BRAF
BRAF (V599E)
Aurora A
CDK2/cycline E
c-Kit
c-Met
EGFR
EGFR (L858R)
EGFR (L858R T790M)
EGFR (T790M)
EPHA2
0.2
0.4
20
26
>3000
6.4
>3000
>3000
736
231
>3000
>3000
0.6
FGFR3
FGFR4
VEGFR1
VEGFR2
VEGFR3
FMS
IR
JAK1
JAK2
JAK3
10.5
34
5.2
2.3
2.6
7.2
>3000
55.3
536
57.5
2.0
<0.15
1.3
2.6
2. O’Hare, T.; Eide, C. A.; Deininger, M. W. Blood 2007, 110, 2249.
3. (a) Weisberg, E.; Manley, P. W.; Breitenstein, W.; Brueggen, J.; Cowan-Jacob, S.
W.; Ray, A.; Huntly, B.; Fabbro, D.; Fendrich, G.; Hall-Meyers, E.; Kung, A. L.;
Mestan, J.; Daley, G. Q.; Callahan, L.; Catley, L.; Cavazza, C.; Mohammed, A.;
Neuberg, D.; Wright, R. D.; Gilliland, D. G.; Griffin, J. D. Cancer Cell 2005, 7, 129;
(b) Shah, N. P.; Tran, C.; Lee, F. Y.; Chen, P.; Norris, D.; Sawyers, C. L. Science
2004, 305, 399.
FLT3
LYN
PDGFR
a
EPHA3
1.2
PDGFRb
EPHA7
FGFR1
FGFR2
4.2
1.8
1.5
RET
Tie2/TEK
Src
0.2
2.2
4.0
4. (a) O’Hare, T.; Walters, D. K.; Stoffregen, E. P.; Jia, T.; Manley, P. W.; Mestan, J.;
Cowan-Jacob, S. W.; Lee, F. Y.; Heinrich, M. C.; Deininger, M. W. N.; Druker, B. J.
Cancer Res. 2005, 65, 4500; (b) Deguchi, Y.; Kimura, S.; Ashihara, E.; Niwa, T.;
Hodohara, K.; Fujiyama, Y.; Maekawa, T. Leuk. Res. 2008, 32, 980; (c) Redaelli, S.;
Piazza, R.; Rostagno, R.; Magistroni, V.; Perini, P.; Marega, M.; Gambacorti-
Passerini, C.; Boschelli, F. J. Clin. Oncol. 2009, 27, 469.
5. Huang, W.-S.; Zhu, X.; Wang, Y.; Azam, M.; Wen, D.; Sundaramoorthi, R.;
Thomas, R. M.; Liu, S.; Banda, G.; Lentini, S. P.; Das, S.; Xu, Q.; Keats, J.; Wang, F.;
Wardwell, S.; Ning, Y.; Snodgrass, J. T.; Broudy, M. I.; Russian, K.; Daley, G. Q.;
Iuliucci, J.; Dalgarno, D. C.; Clackson, T.; Sawyer, T. K.; Shakespeare, W. C. J. Med.
Chem. 2009, 52, 4743.
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Adrian, L. T.; Zhou, T.; Huang, W.-S.; Xu, Q.; Metcalf, C. A.; Tyner, J. W.; Loriaux,
M. M.; Corbin, A. S.; Wardwell, S.; Ning, Y.; Keats, J. A.; Wang, Y.;
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7. Huang, W.-S.; Metcalf, C. A.; Sundaramoorthi, R.; Wang, Y.; Zou, D. R.; Thomas,
M.; Zhu, X.; Cai, L.; Wen, D.; Liu, S.; Romero, J.; Qi, J.; Chen, I.; Banda, G.; Lentini,
S. P.; Das, S.; Xu, Q.; Keats, J.; Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J. T.;
Broudy, M. I.; Russian, K.; Zhou, T.; Commodore, L.; Narasimhan, N.;
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Romero, J.C. PCT Int. Appl. WO2007133562.
In summary, we describe a strategy to design an orthogonal ser-
ies of BCR–ABL inhihitors bearing monocyclic hinge-binding tem-
plates, evolved from our clinical candidate and pan-BCR–ABL
inhibitor, ponatinib. Lead compounds from this series potently in-
hibit ABL kinase activity and proliferation of Ba/F3 cells expressing
both native BCR–ABL and BCR–ABLT315I with low nM IC50s. Multi-
ple compounds in the series exhibited favorable rat and mouse
pharmacokinetic profiles, and 8h exhibited efficacy similar to
ponatinib in an aggressive mouse model of CML driven by the
T315I mutant of BCR–ABL. The additional hinge region H-bond ap-
pears to compensate for the decreased hydrophobic interactions of
the monocycle relative to the 6,5-fused bicycle in ponatinib in
terms of in vitro and in vivo activity, and has almost no effect on
kinase selectivity. Monocyclic derivatives such as 8h may be useful
for targeting multiple kinases, including those bearing gatekeeper
mutations, and therefore could prove useful in the treatment of
tumor types where these kinases play a key role.
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The authors thank Narayana Narasimhan and Manfred Weigele
from ARIAD for useful discussions.