Accelerated Discovery of Macrocyclic CDK2 Inhibitor QR-6401 by Generative Models and Structure-Based Drug Design

Yu, Yang; Huang, Junhong; He, Hu; Han, Jing; Ye, Geyan; Xu, Tingyang; Sun, Xianqiang; Huang, Jianwen; Ren, Xiaoming; Li, Chunlai; Li, Huijuan; Huang, Wei; Liu, Yangyang; Wang, Xinjuan; Gao, Yongzhi; Cheng, Nianhe; Guo, Ning; Chen, Xibo; Feng, Jian-Xia; Yang, Hua; Liu, Chong; Zhu, Guoyun; Xie, Zhi; Yao, Lili; Zhong, Wenge; Chen, Xinde; Liu, Wei; Li, Hailong

doi:10.1021/acsmedchemlett.2c00515

Cited by 16 publications

(14 citation statements)

References 35 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The high cancer relevance of CCNE1 has motivated efforts to discover small molecules that can inhibit CCNE1:CDK2 complexes. While orthosteric (ATP site-competitive) CDK2 inhibitors have been described 36,37,38 , these compounds face selectivity challenges across the CDK family and broader kinome and also do not discriminate among the various cyclin (A and E-type):CDK2 complexes. We reasoned that the NanoBRET-ABPP assay could identify alternative types of reversibly binding compounds to N112C-CCNE1:CDK2 complexes that would also have the potential to bind WT-CCNE1:CDK2 complexes.…”

Section: Resultsmentioning

confidence: 99%

Expanding the ligandable proteome by paralog hopping with covalent probes

Zhang,

Liu,

Hirschi

et al. 2024

Preprint

View full text Add to dashboard Cite

More than half of the ~20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling (ABPP) that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-N112C-CCNE1 interaction into a NanoBRET-ABPP assay capable of identifying compounds that reversibly inhibit both N112C- and WT-CCNE1:CDK2 complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings thus provide a roadmap for leveraging electrophile-cysteine interactions to extend the ligandability of the proteome beyond covalent chemistry.

show abstract

Section: Resultsmentioning

confidence: 99%

Expanding the ligandable proteome by paralog hopping with covalent probes

Zhang,

Liu,

Hirschi

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…We utilize PMDM to perform scaffold hopping on compound 13 complexed with CDK2 (PDB ID: 8H6T) to develop potential inhibitors 54 . The reference compound 13 is illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…6 a) and reserve the remaining fragment as the seed scaffold (Fig. 6 a) which is the key scaffold of the existing CDK2 inhibitors 54 , 55 . Finally, we leverage PMDM to generate a library of 10000 molecules for relacing the essential fragments.…”

Section: Resultsmentioning

confidence: 99%

A dual diffusion model enables 3D molecule generation and lead optimization based on target pockets

Huang,

Xu,

et al. 2024

Nat Commun

Self Cite

View full text Add to dashboard Cite

Structure-based generative chemistry is essential in computer-aided drug discovery by exploring a vast chemical space to design ligands with high binding affinity for targets. However, traditional in silico methods are limited by computational inefficiency, while machine learning approaches face bottlenecks due to auto-regressive sampling. To address these concerns, we have developed a conditional deep generative model, PMDM, for 3D molecule generation fitting specified targets. PMDM consists of a conditional equivariant diffusion model with both local and global molecular dynamics, enabling PMDM to consider the conditioned protein information to generate molecules efficiently. The comprehensive experiments indicate that PMDM outperforms baseline models across multiple evaluation metrics. To evaluate the applications of PMDM under real drug design scenarios, we conduct lead compound optimization for SARS-CoV-2 main protease (Mpro) and Cyclin-dependent Kinase 2 (CDK2), respectively. The selected lead optimization molecules are synthesized and evaluated for their in-vitro activities against CDK2, displaying improved CDK2 activity.

show abstract

“…Macrocyclic compounds are primitive structural motifs in biologically active natural products, [1] pharmaceutically active compounds [2,3] and the perfume industry. [4] In addition to the medicinal applications, structurally distinct macrocycles have applications in chemistry, such as supramolecular chemistry, [5] materials science [6] and phase transfer catalysis.…”

Section: Introductionmentioning

confidence: 99%

Direct Intramolecular Coupling of Primary/Secondary Alcohols with Secondary Alcohols for Macrocyclic Alkenylation Using Ni‐Zeolite Catalyst Under Continuous‐Flow Conditions

Sutar,

Swami,

Jamdade

et al. 2024

Adv Synth Catal

View full text Add to dashboard Cite

Herein, we report the direct intramolecular coupling of primary and secondary alcohols for the selective synthesis of macrocyclic olefins in the presence of Ni‐zeolite catalyst under continuous flow. This reaction proceeds via dehydration of secondary alcohols to alkenes, which subsequently undergo intramolecular dehydrative coupling reaction with a primary alcohol to obtain moderate yields of macrocyclic olefins. This reaction is also effective for the coupling of secondary‐secondary alcohols and alkene‐alcohols to produce diverse macrocyclic olefin products. This unique approach has various advantages including step‐economy, no additives and pre‐functionalization required, inexpensive and reusable catalysts, and exemplification with 23 macrocycles in different ring sizes. The continuous flow macrocyclisation afforded higher productivity and space‐time yield than the batch reaction conditions.

show abstract

Accelerated Discovery of Macrocyclic CDK2 Inhibitor QR-6401 by Generative Models and Structure-Based Drug Design

Cited by 16 publications

References 35 publications

Expanding the ligandable proteome by paralog hopping with covalent probes

Expanding the ligandable proteome by paralog hopping with covalent probes

A dual diffusion model enables 3D molecule generation and lead optimization based on target pockets

Direct Intramolecular Coupling of Primary/Secondary Alcohols with Secondary Alcohols for Macrocyclic Alkenylation Using Ni‐Zeolite Catalyst Under Continuous‐Flow Conditions

Contact Info

Product

Resources

About