Nicotinamide-Ponatinib, HSN748, a Potent Anti-CML and Anti-AML Compound with Better Kinase Selectivity than Ponatinib

Ponatinib is a multikinase inhibitor that is used to treat chronic myeloid leukemia patients harboring mutated ABL1(T315I) kinase. Due to the potent inhibition of FLT3, RET and FGFRs, it is also being evaluated against AML, biliary and lung cancers. The multikinase inhibition profile of ponatinib may also account for its toxicity, thus analogs with improved kinase selectivity could be better tolerated. A nicotinamide analog of ponatinib, HSN748, retains activity against FLT3, ABL1, VEGFRs and PDGFRa/b but losses activity against c-Src, FGFRs and P38a. Since Src or FGFR inhibitions are known to lead to platelet disfunction or cardiovascular toxicities respectively, HSN748 might have a better safety profile than ponatinib and deserves further evaluation as a possible CML or AML therapeutic.</p

Soluble and Reusable Poly(norbornene) Supports with High Loading Capacities for Peptide Synthesis

Poly(norbornene) supports comprising solubilizing ethylene glycol units and multiple amino acid attachment sites have been developed for peptide synthesis. A variety of amino acids have been efficiently loaded (0.6–1.1 mmol/g) onto the support in high yields (83–98%). Several tripeptides have been synthesized in moderate-to-good overall yields (41–66%) using only 1.2 equiv of coupling reagents/amino acids, and the support could be efficiently recycled up to 3 times

Soluble Non-Cross-Linked Poly(norbornene) Supports for Peptide Synthesis with Minimal Reagents

Solid-phase peptide synthesis has been an attractive method for synthesizing peptides because it is quick and can be automated. The heterogeneous reaction medium in solid-phase peptide synthesis necessitates the use of large equivalents of reagents to drive the reactions to completion. Peptide synthesis using soluble, yet isolable, supports is an attractive alternative to solid-phase peptide synthesis. Reported herein is a soluble poly­(norbornene)-derived support containing multiple attachment sites for high loading capacities and solubilizing oligoether/alkyl groups. The Ala-attached support has been used to synthesize tri- to octapeptides in 28 to 97% yields using only 1.2 equiv of amino acids and coupling reagents. The acyclic hexapeptide precursor to natural product segatalin A was synthesized in 41% yield on the support using one-eighth of the equivalents of coupling reagents compared to that in reported procedures. The support could be recovered in up to 98% yield after peptide synthesis, and the recovered support was utilized to synthesize tri- and tetrapeptides that contain amino acids other than Ala at the C-terminus in ca. 80% yields