Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utilize hydrophobic tagging technology to develop a CDK4/6 degrader against TNBC. We based on the chemical structure of the major metabolite of a clinically approved CDK4/6 inhibitor, abemaciclib, to synthesize three compounds and evaluated their in vitro cytotoxicity. LPM3770277 stood out as the most promising compound which was further confirmed by a series of binding and CDK4/6 degradation studies. LPM3770277 was able to bind to CDK4/6, and time-dependently and dose-dependently increased CDK4/6 protein degradation. Mechanistic study revealed that LPM3770277 exerted its CDK4/6 degradation effect via two machineries: proteasome and lysosome-promoted autophagy. Using in vivo TNBC xenograft cancer model, we found that LPM3770277 demonstrated superior anti-tumor efficacy and safety as compared to abemaciclib, although both compounds exerted similar effects on cell cycle arrest. In conclusion, this study for the first time developed and characterized a CDK4/6 degrader against TNBC using hydrophobic tags, which strongly suggests the viability of hydrophobic tags as a strategy to develop potential treatments against TNBC.
Aim: To separate and evaluate 9-cyclopropylmethoxy-dihydrotetrabenazine (13a) and its stereoisomers for their high affinity for vesicular monoamine transporter-2 (VMAT2). Method: Stereoisomers of 13a were separated and configurations were ascertained by chiral chromatography and crystal diffraction combined with 1H-1H NOESY assay. Possible binding modes of eight stereoisomers and VMAT2 were explored by molecular docking assays. The VMAT2 affinity of the stereoisomers, inhibition in vivo and pharmacokinetics in rats were evaluated. Results: Three stereoisomers were obtained: P1, P2 and P3, and all had similar VMAT2 binding modes. P2 [(2 R, 3 R, 11b R)-13a] showed the highest potential VMAT2 binding activity ( Ki = 0.75 nM), decreased locomotor activity in rats and had an oral absolute bioavailability of 92.0%. Conclusion: P2 has good efficacy and pharmacokinetic properties and warrants further development to treat tardive dyskinesia.
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