ACS Medicinal Chemistry Letters
Letter
dramatic PD response extended well beyond the availability of
drug in plasma and is in line with the slow off-rate observed in
vitro. Encouraged by this result, compound 2 was progressed to
a 14-day efficacy study in the same model. Tumor growth
inhibition (TGI)17 of 66% was observed at a remarkably low,
intermittent, and well-tolerated dose of 2 mg/kg given orally
once every 7 days (Figure 3b). For comparison, compound 1
was progressed to a GEO xenograft study where 64% TGI was
observed at a dose of 5 mg/kg QD (Figure 3c). Unlike
compound 2, the intermittent dose for compound 1 did not
show significant TGI (<50%, data not shown), and daily dosing
(QD) was required for efficacy comparable to compound 2
dosed on the intermittent schedule. Taken together, these data
suggest that for these IGF-1R inhibitors, SKR can be optimized
to afford compounds with varying off-rates. Furthermore,
extended off-rates, exemplified by compound 2, can translate to
extended target coverage and in vivo efficacy.
AUTHOR INFORMATION
■
Corresponding Author
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We gratefully acknowledge Dr. Yingjie Li and Ms. Viorica M.
Lazarescu for analytical support; Mr. Paul Maresca, Ms. Brianna
Tokar, Mr. Pete Meyn, Mr. Roy Turton, and the Leads
Discovery Group for conducting in vitro ADMET studies; Ms.
Kristen Chang for supporting cellular assays; the process
chemistry group for providing key intermediates for synthesis
of compounds described in this manuscript; Drs. Maryland
Franklin, Elizabeth Rizzo, and Qun-Sheng Ji for their
overarching contributions to OSI’s IGF-1R programs.
The kinase selectivity of compound 2 was evaluated in-house
by screening against a panel of 192 kinases using a Caliper EZ
Reader mobility shift assay. Compound 2 achieved >90%
inhibition of IGF-1R and IR without significant inhibition
(<50%) of any other kinases in the panel; thus, it is a highly
selective inhibitor. As part of the pharmaceutical development
assessment, compound 2 was also progressed through a series
of preclinical ADMET assays. As shown in Table 3s (see
Supporting Information), it demonstrated robust microsomal
stability in vitro toward multiple species suggesting an expected
low first pass metabolism (mouse microsomal extraction ratios
(ER) of 0.28 translates to low clearance of 5 mL/min/kg in
vivo). Compound 2 has good aqueous solubility especially at a
lower pH, is highly permeable, and has a clean CYP450
inhibition profile against 5 major isoforms. The ligand-
lipophilic efficiency (LLE)19 for compound 2, based on a
preincubation biochemical IC50 value of 0.6 nM, is favorable at
5.13. These promising physicochemical properties, taken
together with encouraging pharmacological results both in
vitro and in vivo, suggest overall favorable drug-like properties
for compound 2.
In summary, a series of small molecule IGF-1R inhibitors
with unique time-dependent inhibition and slow dissociation
kinetics were discovered and developed. Both SAR and SKR
were established through a systematic medicinal chemistry
effort. Representative compounds were progressed into in vivo
PD/efficacy studies. Most notably, compound 2, a highly
potent, selective, and orally bioavailable IGF-1R slow off-rate
inhibitor, produced significant tumor growth inhibition at a
remarkably low, intermittent dose. Analysis of in vitro and in
vivo data generated from compounds 1 and 2 demonstrate that
drug-receptor off-rates can dramatically influence the overall
profile of a drug molecule. These studies underscore the
importance of incorporating characterization of binding kinetics
into the drug discovery process.
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ASSOCIATED CONTENT
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S
* Supporting Information
Table 1s, Table 3s, synthetic procedure, analytical data for
compound 1 and 2, and procedures for in vitro and in vivo
assays. This material is available free of charge via the Internet
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dx.doi.org/10.1021/ml400160a | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX