Orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, for the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled, phase Ib/IIa study

Xue Li, Ru Li, Xiaoxia Zhu et al.

Research Square Preprint, 23 July 2025,

https://doi.org/10.21203/rs.3.rs-7058001/v1

Orelabrutinib is a highly selective, irreversible inhibitor of Bruton’s tyrosine kinase (BTK). It has shown promising results in animal models, indicating potential for treating systemic lupus erythematosus (SLE). A multicentre, double-blind, randomised, placebo-controlled, phase Ib/IIa trial (NCT04305197) was conducted. Sixty SLE patients were randomised 1:1:1:1 to receive oral orelabrutinib (50, 80, 100 mg) or placebo once daily for 12 weeks. A total of 55 patients completed the trial. In all evaluable patients, the SRI-4 rates at week 12 were 50%, 62%, and 64% for orelabrutinib at 50 mg, 80 mg, and 100 mg, respectively, compared with 36% for placebo. Among patients with baseline SLEDAI-2K > 8, significantly higher SRI-4 responses were noted with orelabrutinib at 50 mg (80%, p = 0·048), 80 mg (83%, p = 0·048), and 100 mg (100%, p = 0·029) compared to placebo (0%). Adverse events were mostly mild or moderate in the study. In summary, orelabrutinib was effective and well-tolerated in SLE patients.

State-of-the-art covalent virtual screening with AlphaFold3

Yoav Shamir, Nir London

bioRxiv 2025.03.19.642201

doi: https://doi.org/10.1101/2025.03.19.642201

Recent years have seen an explosion in the prominence of covalent inhibitors as research and therapeutic tools. However, a lag in application of computational methods for covalent docking slows progress in this field. AI models such as AlphaFold3 have shown accuracy in ligand pose prediction but were never assessed for virtual screening. We show that AlphaFold3 reaches near-perfect classification (average AUC=98.3%) of covalent active binders over property-matched decoys, dramatically outperforming classical covalent docking tools. We identify a predicted metric that allows to reliably assign a probability of binding and demonstrate it also improves non-covalent virtual screening.

The structure of KRASG12C bound to divarasib highlights features of potent switch-II pocket engagement

Fernando, M. C., Craven, G. B., & Shokat, K. M. 

Small GTPases, 2024 15(1), 1–7. 

https://doi.org/10.1080/21541248.2025.2505441

KRAS is the most frequently mutated oncogene in human cancer. In multiple types of cancer, a missense mutation at codon 12 substitutes a glycine for a cysteine, causing hyperactivation of the GTPase and enhanced MAPK signalling. Recent drug discovery efforts culminating from work during the past decade have resulted in two FDA-approved inhibitors, sotorasib and adagrasib, which target the KRASG12C mutant allele. Ongoing medicinal chemistry efforts across academia and industry have continued developing more potent and efficacious KRASG12C inhibitors. One agent in late-stage clinical trials, divarasib, has demonstrated robust overall response rates, in some cases greater than currently approved agents. Divarasib also exhibits enhanced covalent target engagement in vitro and significant specificity for KRASG12C, yet the structural details of its binding have not been published. Here we report a high-resolution crystal structure of cysteine-light KRAS-4BG12C in complex with divarasib. Though it binds in the same allosteric pocket as sotorasib and adagrasib, the switch-II loop in each crystal structure takes on a distinct conformation differing as much as 5.6 Å between the Cα atom of residue 65 with sotorasib. Additionally, we highlight structural features of the drug complex that may guide future medicinal chemistry efforts targeting various KRAS alleles.

Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders

Nathanael Schiander Gray, Zhe Zhuang, Woong Sub Byun, Zuzanna Kozicka, Katherine Donovan, Brendan Dwyer, Abby Thornhill, Hannah Jones, Zixuan Jiang, Xijun Zhu, Eric Fischer, Nicolas Thomä, 

Angew. Chem. Int. Ed. 2025, e202508427.

https://doi.org/10.1002/anie.202508427

Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease-related proteins. While molecular glue degraders exhibit drug-like properties, their discovery has traditionally been serendipitous and often requires post-hoc rationalization. In this study, we demonstrate the rational, mechanism-guided design of molecular glue degraders using gluing moieties. Building on established principles, by appending a chemical gluing moiety to several small molecule inhibitors, we successfully transformed them into degraders, obviating the need for a specific E3 ubiquitin ligase recruiter. Specifically, we found that incorporating a hydrophobic aromatic ring or a double bond into a cyclin-dependent kinase 12 and 13 (CDK12/13) dual inhibitor enabled the recruitment of DNA damage-binding protein 1 (DDB1), thereby transforming a high-molecular-weight bivalent CDK12 degrader into a potent monovalent CDK12/13 molecular glue degrader. We also showcase that attaching a cysteine-reactive warhead to a bromodomain-containing protein 4 (BRD4) inhibitor converts it into a degrader by recruiting the DDB1 and CUL4 associated factor 16 (DCAF16) E3 ligase.

Discovery of the Clinical Candidate S-892216: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19

Yuto Unoh, Keiichiro Hirai, Shota Uehara, Sho Kawashima, Haruaki Nobori, Jun Satom, Hiromitsu Shibayama, Akihiro Hori, Kenji Nakahara, Kana Kurahashi, Masayuki Takamatsu, Shiho Yamamoto, Qianhui Zhang, Miki Tanimura, Reiko Dodo, Yuki Maruyama, Hirofumi Sawa, Ryosuke Watari, Tetsuya Miyano, Teruhisa Kato, Takafumi Sato,Yuki Tachibana

J. Med. Chem. 2025

https://doi.org/10.1021/acs.jmedchem.5c00754

The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health and an unmet need for therapeutic options. Herein, we report the discovery of S-892216, a second-generation SARS-CoV-2 3C-like protease (3CLpro) inhibitor, to treat COVID-19. S-892216 is a reversible covalent 3CLpro inhibitor with highly potent antiviral activity and an EC50 value of 2.48 nM against SARS-CoV-2 infected cells. Structure-based design of a covalent modifier for compound 1 revealed that introducing a nitrile warhead increased 3CLpro inhibition activity by 180-fold. Subsequent optimization efforts yielded S-892216, which combined a favorable pharmacokinetic profile and high off-target selectivity. S-892216 exhibited antiviral activity against diverse SARS-CoV-2 variants, including major mutations reducing antiviral activities of nirmatrelvir and ensitrelvir. In SARS-CoV-2-infected mice, S-892216 inhibited viral replication in the lungs similar to ensitrelvir, although at a 30-fold lower dose.