We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
Isocyanates 7 were formed from monoprotected diamines
3 or 6, which in turn can be easily
prepared
from commercially available N-BOC- or
N-FMOC-protected amino acid derivatives. Isocyanates
7, formed in
situ,
could be coupled directly to a solid support functionalized with amine
groups or to amino acids anchored on resins
using CH2Cl2 as solvent and an 11 h
coupling time at 25 °C. Such couplings afforded peptidomimetics
with an
N-phthaloyl group at the N-terminus. The
optimal conditions identified for removal of the N-phthaloyl
group were
to use 60% hydrazine in DMF for 1−3 h. Several sequences of
amino acids coupled to ureas (“peptidic ureas”) and
of sequential urea units (“oligoureas”) were prepared via solid
phase syntheses and isolated by HPLC. Partition
coefficients were measured for two of these peptidomimetics, and their
water solubilities were found to be similar
to the corresponding peptides. A small library of 160 analogues of
the YGGFL-amide sequence was prepared via
Houghten's tea bag methodology. This library was tested for
binding to the anti-β-endorphin monoclonal
antibody.
Overall, this paper describes methodology for solid phase
syntheses of oligourea derivatives with side chains
corresponding to some of the protein amino acids. The chemistry
involved is ideal for high-throughput syntheses
and screening operations. The products can be expected to have an
interesting range of pharmacological properties
and enhanced proteolytic stabilities relative to the corresponding
peptides.
This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.
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