Discovery of YK-029A, a novel mutant EGFR inhibitor targeting both T790 M and exon 20 insertion mutations, as a treatment for NSCLC.

Although traditional EGFR-TKIs have advanced the treatment landscape of NSCLC with sensitive driver mutations (del19 or L858R), some NSCLC patients with EGFR exon 20 insertion mutations have been left with few effective therapies. The development of novel TKIs is still in progress. Herein, we describe the structure-guided design of a novel selective and orally bioavailable inhibitor, YK-029A, which could overcome both the T790 M mutations and exon 20 insertion of EGFR. YK-029A inhibited EGFR signaling, suppressed sensitive mutations and ex20ins of EGFR-driven cell proliferation, and was largely effective with oral administration in vivo. Furthermore, YK-029A exhibited significant antitumor activity in EGFRex20ins-driven patients-derived xenograft (PDX) models, preventing tumor progression or causing tumor regression at well-tolerated dosages. Based on the outcomes of preclinical efficacy and safety studies, YK-029A will enter phase Ⅲ clinical trials for the treatment of EGFRex20ins NSCLC.

Emission reductions, industrial competitiveness, and spillover effects under China's regional emission trading systems: Evidence from the iron and steel sector.

An emission trading system (ETS) has been consistently recognized as a promising instrument to stem massive carbon emissions from energy-intensive industries. However, it remains ambiguous whether the ETS can achieve emission mitigation without undermining economic activity in specific industries in emerging running markets. This study focuses on the impact of China's four independent ETS pilots on carbon emissions, industrial competitiveness, and spatial spillover effects in the iron and steel industry. With a synthetic control method for causal inference, we find that the achievement of emission reductions was generally accompanied by losses of competitiveness in the pilot regions. An exception to this trend was seen in the Guangdong pilot, where the aggregate emissions increased due to the incentivized output created by a specific benchmarking allocation approach. Despite impaired competitiveness, the ETS did not cause significant spatial spillovers, which alleviates concerns about potential carbon leakage under unilateral climate regulation. Our findings could enlighten subsequent sector-specific assessments of the effectiveness of ETSs and are also valuable to policymakers in and outside China now considering ETSs.

Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile.

We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).

Discovery of N-benzyl-N'-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (I): optimization of the amine portion.

Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series.

Discovery of N-benzyl-N'-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (II): modification of the acyl portion.

Modification of the acyl moiety in the CCR5 lead molecule 2 led to identification of several new classes of CCR5 antagonists. Antiviral activity and pharmacokinetic properties of the synthesized compounds were evaluated. Structure-activity relationship (SAR) derived from these studies further guided the optimization efforts, ultimately leading to the discovery of 36 with an acceptable drug-like profile.

4,4-Disubstituted cyclohexylamine based CCR5 chemokine receptor antagonists as anti-HIV-1 agents.

A series of 4,4-disubstituted cyclohexylamine based CCR5 antagonists has been designed and synthesized. Their antiviral structure-activity relationship has been extensively explored.