Inhibition of methionine adenosyltransferase 2A (MAT2A) in cancers with a deletion of methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality, thus receiving significant interest in the field of precise cancer treatment. Herein, we report the discovery of a tetrahydrobenzo [4,5]imidazo-[1,2-a]pyrazine fragment which occupies the MAT2A allosteric pocket. The lead compound 8 exhibited extremely high potency to inhibit MAT2A enzymatic activity (IC 50 = 18 nM) and proliferation of MTAP-null cancer cells (IC 50 = 52 nM). 8 had a favorable pharmacokinetic profile with a bioavailability of 116% in mice. More importantly, introducing an amide motif (28) to the core structure raised the plasma drug exposure from 11 718 to 41 192 ng•h•mL −1 . 28 displayed a significantly better in vivo potency than AG-270, which is being evaluated in clinical trails, and induced −52% tumor regression in a xenograft MTAP-depleted colon tumor model.

The major challenges of photothermal therapy (PTT) toward clinical application are the severe skin injury and inflammation response associated with high power laser irradiation. Herein, polydopamine nanoparticles (PDA-EST and PDA-RAL) targeted to estrogen receptor 𝜶 (ER𝜶) for efficient ablation of breast tumor under a low irradiation density of 0.1 W cm -2 are reported. These nanoparticles are capable of recruiting ER𝜶 on their surface and induce a complete ER𝜶 degradation via localized heat. Owing to the ER𝜶 targetability, PDA-EST and PDA-RAL strongly suppress the proliferation of breast cancer cells without causing significant inflammation. This work provides a generalized method for enhancing PTT efficacy under low irradiation density.

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