Chemical modification has been performed on an orally bioavailable and potent CCR5 antagonist, sulfoxide compound 4, mainly focusing on replacement of the [6,7]-fused 1-benzazepine nucleus. We designed, synthesized, and evaluated the biological activities of ring-expanded [6,8]-, [6,9]-, and [6,10]-fused compounds containing S-sulfoxide moieties, which led to the discovery of 1-benzazocine and 1-benzazonine compounds that exhibited potent inhibitory activities (equivalent to compound 4) in a binding assay. In addition, 1-benzazocine compounds possessing the S-sulfoxide moiety ((S)-(-)-5a,b,d,e) showed greater potency than compound 4 in a fusion assay. From further investigation in a multi-round infection assay, it was found that 1-isobutyl-1-benzazocine compound (S)-(-)-5b, containing the S-{[(1-propyl-1H-imidazol)-5-yl]methyl}sulfinyl group, showed the most potent anti-HIV-1 activity (IC90=0.81 nM, in MOLT4/CCR5 cells). Compound (S)-(-)-5b (TAK-652) also inhibited the replication of six macrophage-tropic (CCR5-using or R5) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) (mean IC90=0.25 nM). It was also absorbed after oral administration in rats, dogs, and monkeys and was thus selected as a clinical candidate. The synthesis and biological activity of the 1-benzazocine compound (S)-(-)-5b and its related derivatives are described.

Protein degradation technology based on hybrid small molecules is an emerging drug modality that has significant potential in drug discovery and as a unique method of post-translational protein knockdown in the field of chemical biology. Here, we report the first example of a novel and potent protein degradation inducer that binds to an allosteric site of the oncogenic BCR-ABL protein. BCR-ABL allosteric ligands were incorporated into the SNIPER (Specific and Nongenetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers) platform, and a series of biological assays of binding affinity, target protein modulation, signal transduction, and growth inhibition were carried out. One of the designed compounds, (SNIPER(ABL)-062), showed desirable binding affinities against ABL1, cIAP1/2, and XIAP and consequently caused potent BCR-ABL degradation.

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Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR‐ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long‐term treatment. An alternative approach to treat CML is to downregulate the BCR‐ABL protein. We have devised a protein knockdown system by hybrid molecules named Specific and Non‐genetic inhibitor of apoptosis protein [IAP]‐dependent Protein Erasers (SNIPER), which is designed to induce IAP‐mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR‐ABL protein have been developed recently. In this study, we tested various combinations of ABL inhibitors and IAP ligands, and the linker was optimized for protein knockdown activity of SNIPER(ABL). The resulting SNIPER(ABL)‐39, in which dasatinib is conjugated to an IAP ligand LCL161 derivative by polyethylene glycol (PEG) × 3 linker, shows a potent activity to degrade the BCR‐ABL protein. Mechanistic analysis suggested that both cellular inhibitor of apoptosis protein 1 (cIAP1) and X‐linked inhibitor of apoptosis protein (XIAP) play a role in the degradation of BCR‐ABL protein. Consistent with the degradation of BCR‐ABL protein, the SNIPER(ABL)‐39 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and Crk like proto‐oncogene (CrkL), and suppressed the growth of BCR‐ABL‐positive CML cells. These results suggest that SNIPER(ABL)‐39 could be a candidate for a degradation‐based novel anti‐cancer drug against BCR‐ABL‐positive CML.