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Wepreviously developed highly potent proteasome inhibitor 1(IC50= 5.7 nM) and its nonpeptide derivative 2(IC50= 29 nM) by systematic structure–activityrelationship studies of the peptidic natural product belactosin Aand subsequent rational topology-based scaffold hopping, respectively.Their cell growth inhibitory activities, however, were only moderate(IC50= 1.8 μM (1) and >10 μM(2)). We therefore planned to replace the unstable β-lactonewarhead with a more stable boronic acid warhead. Importantly, belactosinderivatives bind mainly to the proteasome binding site, which is differentfrom that occupied by known peptide boronate proteasome inhibitorssuch as bortezomib, suggesting that their hybridization might leadto the development of novel potent inhibitors. Here we describe design,synthesis, and biological activities of the newly developed potenthybrid proteasome inhibitors. Interestingly, these hybrids, unlikebortezomib, were highly selective for proteasomes and have long residencetimes despite having the same boronic acid warhead. [ABSTRACT FROM AUTHOR]

Todevelop potent covalent inhibitors, the noncovalent interactions aroundthe transition state to form covalent bonding should be optimizedbecause the potency of the inhibitor can be depending on the energyof the transition state. Here, we report an efficient analysis ofthe noncovalent binding mode of a potent covalent proteasome inhibitor 3aaround the transition state by a combined use of the chemicalapproach, i.e., the cyclopropylic strain-based conformational restriction,and the computational docking approach. Furthermore, we calculatedthe binding energy of a series of salinosporamide derivatives in thepredicted noncovalent complex around the transition state with thesimulation model of proteasome constructed in this study, which waswell correlated to their pIC50. Thus, the proposed dockingmethods to predict the noncovalent binding mode around the transitionstate of covalent inhibitors will be helpful toward the developmentof covalent inhibitors. [ABSTRACT FROM AUTHOR]

Thenatural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compoundfor developing potent proteasome (core particle, CP) inhibitors. Todate, 1and its analogues are the only CP ligands thatbind to both the nonprimed S1 pocket as well as the primed substratebinding channel; however, these molecules harbor a high IC50value of more than 1 μM. We have performed structure–activityrelationship studies, thereby elucidating unnatural cis-cyclopropane derivatives of 1that exhibit high potencyto primarily block the chymotrypsin-like active site of the humanconstitutive (cCP) and immunoproteasome (iCP). The most active compound 3ereversibly inhibits cCP and iCP similarly with an IC50of 5.7 nM. X-ray crystallographic analysis of the yeastproteasome in complex with 3erevealed that the ligandis accommodated predominantly into the primed substrate binding channeland covalently binds to the active site threonine residue via itsβ-lactone ring-opening. [ABSTRACT FROM AUTHOR]

The kinesin spindle protein (KSP) is a mitotic kinesin involved in the establishment of a functional bipolar mitotic spindle during cell division. It is considered to be an attractive target for cancer chemotherapy with reduced side effects. Based on natural product scaffold-derived fused indole-based inhibitors and known biphenyl-type KSP inhibitors, various carboline and carbazole derivatives were synthesized and biologically evaluated. β-Carboline and lactam-fused carbazole derivatives exhibited remarkably potent KSP inhibitory activity and mitotic arrest in prometaphase with formation of an irregular monopolar spindle. The planar tri- and tetracyclic analogs inhibited KSP ATPase in an ATP-competitive manner just like biphenyl-type inhibitors. [ABSTRACT FROM AUTHOR]