ACS Medicinal Chemistry Letters
Letter
a
Scheme 2. Preparation of Sulfonamide-Based Inhibitors
a
Reagents and conditions: (a) XPhB(OH)2, Pd(OAc)2, PPh3, aqueous Na2CO3, THF, reflux, 12 h or MW, 150 °C, 30 min for Y = bond; XPhNH2
or XPhNHMe DIPEA, IPA, reflux, 12 h or MW, 150 °C, 30 min for Y = NH or NMe. (b) Chlorosulfonic acid, room temperature or 90 °C, 1−12 h.
(c) R2R3NH, DIPEA, IPA, room temperature, 1 h. (d) R4NH2, Pd2(dba)3, Xantphos, K2CO3, tBuOH, reflux, 12 h.
Funding
Our next approach exploited the differences in the
hydrophobic pockets of the kinases. A favorable hydrophobic
interaction exists in the case of AXL only between the 4-aryl
group and the Leu542 residue in the roof of the β-sheet
forming the hydrophobic pocket. Strengthening this interaction
can be achieved by enhancing the hydrophobic contacts
between the inhibitor and the DGF “in” loop of the kinase,
inducing a slight conformational change, which reduces the
distance between the 4-aryl substituent and the roof of the
hydrophobic pocket residues. To this intent, the N-dimethyl
groups of 13 and 14 were replaced by more lipophilic
pyrrolidinyl or N-cyclopropyl groups (18−20; see Table 2).
This resulted in moderate AXL binding improvement in all
cases, but the Aurora activity did not decrease. The addition of
electron-withdrawing atoms on the 4-aryl ring was also studied
(21−25; synthesis shown in Scheme 2): F was well tolerated
but did not improve activity or selectivity, and Cl resulted in
loss of AXL activity. Methylation of the amine linker also
resulted in loss of activity, presumably as a result of increased
conformational strain. When the aryl ring was directly
connected to the pyrimidine core (15, 16, 26, and 27), potent
AXL inhibitors were obtained, but again, they exhibited strong
aurora activity. Finally, meta-substituted analogues of 13
featuring both NH and C−C bound 4-aryl groups were
prepared, but decreased activities were observed, presumably
due to steric clashes arising from the change in orientation of
the aryl group in the hydrophobic pocket.
In conclusion, we have prepared a series of potent AXL
kinase inhibitors featuring a 5-Cl pyrimidine core carrying an
arylsulfonamide moiety in its 4-position. The pyrimidine
scaffold was chosen based on the results on in silico screening
of fragments and in-house compounds against a homology
model of AXL kinase. Several compounds displayed low
nanomolar activity against AXL in biochemical assays and
potently inhibited the growth of PSN1 cells. However, cell
cycle studies revealed that the compounds induced strong G2/
M arrest by potently inhibiting Aurora A and B as well as
several other kinases. Synthetic efforts are underway to improve
the selectivity profile of our inhibitors while retaining potency.
We acknowledge support from the Huntsman Cancer
Foundation and NCI grant number P30 CA042014.
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ASSOCIATED CONTENT
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S
* Supporting Information
Full experimental procedures and characterization for all
compounds. This material is available free of charge via the
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AUTHOR INFORMATION
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Corresponding Author
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dx.doi.org/10.1021/ml200198x|ACS Med. Chem. Lett. 2011, 2, 907−912