Chemodynamic therapy (CDT) is a cancer treatment that converts endogenous H2O2 into hydroxyl radicals (˙OH) through Fenton reaction to destroy cancer cells.

Targeted protein degradation technologies (e.g., PROTACs) that can selectively degrade intracellular protein are an emerging class of promising therapeutic modalities. Herein, we describe the conjugation of photosensitizers and protein ligands (PS-Degrons), as an activable targeted protein degradation platform. PS-Degrons are capable of degrading protein of interest via light-triggered 1O2, which is orthogonal and complementary to existing technologies. This generalizable platform allows controllable knockdown of the target protein with high spatiotemporal precision. Our lead compound PSDalpha induces a complete degradation of human estrogen receptor α (ERα) under visible light. The high degrading ERα efficacy of PSDalpha enables an excellent anti-proliferation performance on MCF-7 cells. Our results establish a modular strategy for the controllable degradation of target proteins, which can hopefully overcome the systemic toxicity in clinical treatment of PROTACs. We anticipate that PS-Degrons would open a new chapter for biochemical research and for the therapeutics.

The interaction between son of sevenless 1 (SOS1) gene and Kirsten rat sarcoma viral oncogene (KRAS) is crucial for activating signals of proliferation and survival in a range of cancers. We previously discovered compound 40a with a tetracyclic quinazoline pharmacophore as a potent orally bioavailable SOS1 inhibitor. Herein, we disclosed the discovery of compound 13c, which substituted the third ring with the seven-membered ring, as a clinical drug candidate for suppressing KRAS-driven tumors. 13c strongly disrupted the protein–protein interaction between SOS1 and KRAS with low IC50 values of 3.9 nM (biochemical) and 21 nM (cellular). 13c showed a favorable pharmacokinetic profile with a bioavailability of 86.8% in beagles and exhibited 83.0% tumor suppression in Mia-paca-2 pancreas xenograft mice tumor models. 13c exhibited a weak time-dependent CY3A4P inhibition than BI-3406, thereby reducing the risk of drug–drug interaction in drug combination. Toxicological investigations revealed that 13c had a lower risk of sudden cardiac death than BI-3406. Overall, 13c has been under evaluation in preclinical trials.

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.