Discovery of tricyclic PARP7 inhibitors with high potency, selectivity, and oral bioavailability.

PARP7 has been recently identified as an effective drug target due to its specific role in tumor generation and immune function recovery. Herin, we report the discovery of compound 8, which contained a tricyclic fused ring, as a highly selective PARP7 inhibitor against other PARPs. In particular, compound 8 strongly inhibits PARP7 with an IC50 of 0.11 nM, and suppresses the proliferation of NCI-H1373 lung cancer cells with an IC50 of 2.5 nM. Compound 8 exhibits a favorable pharmacokinetic profile with a bioavailability of 104 % in mice, and 78 % in dogs. Importantly, daily treatment of 30 mg/kg of 8 induced 81.6 % tumor suppression in NCI-H1373 lung xenograft mice tumor models, which is significantly better than the clinical candidate, RBN-2397. These intriguing features highlight the promising advantages of 8 as an antitumor agent.

Exploring the structural-activity relationship of hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine derivatives as potent and orally-bioavailable PARP7 inhibitors.

PARP7 has emerged as a promising anti-tumor target due to its crucial roles in nucleic acid sensing and immune regulation. Herein, we explored the structural-activity relationship of tricyclic PARP7 inhibitors containing a hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine motif. The effects of the chirality of the fused rings, the group conjugated to the fused rings, and the size of the linker on PARP7 inhibition were fully investigated. Our work leads to the discovery of an extremely potent and orally-bioavailable PARP7 inhibitor, namely 18 (PARP7 inhibition IC50 = 0.56 nM), for efficacious treatment of lung cancer in vivo. Notably, 18 showed acceptable bioavailability in ICR mice (F = 33.9%) and Beagle dogs (F = 45.2%). Further investigation of ADME-T properties suggested that 18 has the potential to be developed as a candidate drug molecule for PARP7-sensitive tumors.

Design of Orally-bioavailable Tetra-cyclic phthalazine SOS1 inhibitors with high selectivity against EGFR.

KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many deadliest cancers. Son of sevenless homolog 1 (SOS1) is a crucial regulator of KRAS to modulate KRAS from inactive to active states. We previously discovered tetra-cyclic quinazolines as an improved scaffold for inhibiting SOS1-KRAS interaction. In this work, we report the design of tetra-cyclic phthalazine derivatives for selectively inhibiting SOS1 against EGFR. The lead compound 6c displayed remarkable activity to inhibit the proliferation of KRAS(G12C)-mutant pancreas cells. 6c showed a favorable pharmacokinetic profile in vivo, with a bioavailability of 65.8% and exhibited potent tumor suppression in pancreas tumor xenograft models. These intriguing results suggested that 6c has the potential to be developed as a drug candidate for KRAS-driven tumors.

Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability.

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 (IC50 = 18 nM) and proliferation of MTAP-null cancer cells (IC50 = 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.

Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma.

KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many refractory cancers. Son of sevenless homolog 1 (SOS1) is a key regulator of KRAS to modulate KRAS from inactive to active states. Herein, we disclosed efficacy-improving tetra-cyclic quinazoline derivatives as an enhanced scaffold for inhibiting the SOS1-KRAS interaction. Compound 37, which conjugated 1-carbonitrile-cyclopropane to tetra-cyclic quinazoline, showed a twofold higher oral drug exposure and 2.5-fold longer half-life than BI-3406 in CD-1 mouse plasma. In a Mia-paca-2 xenograft model, 37 administrated alone inhibited tumor growth by 71%. Preclinical investigations demonstrated that 37 had a limited inhibition of CYP and hERG. Overall, our studies showed that 37 was a promising drug candidate for treatment of KRAS-driven cancer.

Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma.

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.

Transport and retention of copper oxide nanoparticles under unfavorable deposition conditions caused by repulsive van der Waals force in saturated porous media.

Currently, copper oxide nanoparticles (CuO NPs) have been widely used in industry, manufacturing and agriculture. The transport and retention of CuO NPs are vital to understanding the fate as well as the life cycle of CuO NPs in the environment. This study systematically investigates the transport and retention of CuO NPs in saturated porous media, and the experimental results were explained by the CFT and DLVO theory. The van der Waals force between CuO NPs and collector was repulsive, resulting in the unfavorable deposition condition. Column experiments were conducted with saturated quartz sand under environmentally relevant pH (6, 8, 9), ionic strength (IS, 1, 10, 50 mM), and humic acid (HA, 0.1-10 mg-C/mL). Experimental results show that the breakthrough curves (BCTs) were affected by different pH and IS. Under pH 6 and 9, the mobility of CuO NPs was enhanced by high IS while the mobility was inhibited by high IS under pH 8. The mobility of CuO NPs was enhanced by humic acid and the effect was best at 0.5 mg-C/mL HA. The experimental results were successfully explained by CFT and DLVO theory, the main mechanisms were aggregation of CuO NPs, interaction energy and collision between CuO NPs and collector. In general, these findings can improve our understanding of the transport and retention of CuO NPs in subsurface environments, and suggest pH, IS, HA may be key factors governing mobility and stability of CuO NPs in natural environment.

Effects of Copper Oxide Nanoparticles on Paddy Soil Properties and Components.

The wide use of metal-based nanoparticles (MNPs) will inevitably lead to their release into soil, and consequently affect the quality and ecological functions of soil environments. In this study, two paddy soils with different properties were exposed to CuO NPs to evaluate the transformation of CuO NPs and their effects on soil properties and components. The results of single chemical extraction and X-ray absorption fine structure analysis showed that CuO NPs could release Cu ions once being applied into the flooding paddy soil and then progress toward the more stable forms (Cu2S and Cu(OH)2). CuO NPs could change the soil properties by increasing the pH and Eh of the lower organic matter-soil rather than those of the higher organic matter-soil. Furthermore, we found that the 1000 mg/kg CuO NPs could accelerate the degradation or mineralization of the organic matter, as well as the Fe reduction process, by increasing the Fe(II) content by 293% after flooding for 60 days in the lower organic matter soil. The microbial biomass in both soils was severely inhibited by CuO NPs and the organic matter could partly mitigate the negative effects of CuO NPs.

Mechanism study of sulfur fertilization mediating copper translocation and biotransformation in rice (Oryza sativa L.) plants.

Metabolism of sulfur (S) is suggested to be an important factor for the homeostasis and detoxification of Cu in plants. We investigated the effects of S fertilizers (S0, Na2SO4) on Cu translocation and biotransformation in rice plants by using multiple synchrotron-based techniques. Fertilization of S increased the biomass and yield of rice plants, as well as the translocation factor of Cu from root to shoot and shoot to grain, resulting in enhanced Cu in grain. Sulfur K-edge X-ray near edge structure (XANES) analysis showed that fertilization of S increased the concentration of glutathione in different rice tissues, especially in rice stem and leaf. Copper K-edge XANES results indicated that a much higher proportion of Cu (I) species existed in rice grain than husk and leaf, which was further confirmed by soft X-ray scanning transmission microscopy results. Sulfur increased the proportion of Cu (I) species in rice grain, husk and leaf, suggesting the inducing of Cu (II) reduction in rice tissues by S fertilization. These results suggested that fertilization of S in paddy soils increased the accumulation of Cu in rice grain, possibly due to the reduction of Cu (II) to Cu (I) by enhancing glutathione synthesis and increasing the translocation of Cu from shoot to grain.

Natural organic matter-induced alleviation of the phytotoxicity to rice (Oryza sativa L.) caused by copper oxide nanoparticles.

Natural organic matter (NOM) can interact with engineered nanoparticles (NPs) in the environment and modify their behavior and toxicity to organisms. In the present study, the phytotoxicity of copper oxide (CuO) NPs to rice seedlings in the presence of humic acid as a model NOM was investigated. The results showed that CuO NPs induced the inhibition of root elongation, aberrations in root morphology and ultrastructure, and losses of cell viability and membrane integrity. The adverse effects partly resulted from the generation of reactive oxygen species caused by CuO NPs, which led to lipid peroxidation, mitochondrial dysfunction, and programmed cell death in rice seedlings. However, all the phytotoxicity was alleviated with the addition of humic acid because humic acid coatings on nanoparticle surfaces enhanced electrostatic and steric repulsion between the CuO NPs and the plant cell wall/membrane, reducing contact between NPs and plant and CuO NP-induced oxidative damage to plant cells. The present study's results shed light on the mechanism underlying NP phytotoxicity and highlight the influence of NOM on the bioavailability and toxicity of NPs.

MITIGATION OF Cu(II) PHYTOTOXICITY TO RICE (ORYZA SATIVA) IN THE PRESENCE OF TiO2 AND CeO2 NANOPARTICLES COMBINED WITH HUMIC ACID.

Engineered nanoparticles (NPs) and natural organic matter (NOM) in the environment may interact with background contaminants such as heavy metals and modify their bioavailability and toxicity. In the present study, the combined influences of 2 common NPs (TiO2 and CeO2 ) and humic acid (HA; as a model NOM) on Cu(II) phytotoxicity to rice were investigated by a 3-d root elongation assay performed on filter paper media. The results showed that the adsorption coefficients of bare TiO2 and CeO2 NPs (100 mg/L) toward Cu(2+) are 2.65 and 4.37, respectively, at an initial concentration of 10 mg/L, suggesting that Cu(II) could be strongly adsorbed by NPs, whereas HA-coated TiO2 and CeO2 NPs further enhanced the adsorption coefficients to 4.37 and 6.85, respectively. In addition, compared with Cu-alone treatment, the addition of bare TiO2 and CeO2 NPs (1000 mg/L) increased the length of rice root by 32.5% and 39.0%, respectively; however, the presence of HA-coated TiO2 and CeO2 NPs increased the root length by 90.2% and 100.1%, respectively, which indicated that the mitigation effect of HA-coated NPs on Cu(II) phytotoxicity was more visible than that of bare NPs. The results demonstrated that coexistence of NPs and HA significantly alleviated Cu(II) phytotoxicity as a result of a decrease in bioavailable soluble Cu(II) concentration, which contributes to an understanding of the potential behavior of NPs in the environment.

Synthesis of dehydroabietic acid-modified chitosan and its drug release behavior.

A new type of chitosan derivative, dehydroabietic acid-modified chitosan (DAMC), was synthesized by the acylation reaction of chitosan with dehydroabietic acid chloride (DHAC) under microwave irradiation. The resulting product (DAMC) was characterized by FT-IR, UV, (1)H NMR, X-ray diffraction (XRD), scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), and elemental analysis. The degree of substitution (DS) of DAMC was 16.5%. And chitosan and DAMC were used as carriers of fenoprofen calcium (FC), and their controlled release behavior in artificial intestinal juice was studied. The results showed that the controlled release of FC from the carrier of DAMC is better than that from original chitosan.