Novel Lactams as Cbl-b Inhibitors for Treating Cancer

Sabnis, R. W.

doi:10.1021/acsmedchemlett.2c00413

Cited by 5 publications

(5 citation statements)

References 4 publications

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“…To further understand the unique binding and unbinding kinetics, we performed RAMD 25,26 to study the ligand dissociation and the trajectories from which both bound states and the dissociation pathways can be analyzed. We collected 49 ligands with various activity and selectivity from patents from NURIX 27,28 , HOTSPOT 29,30 , GENTECH 31,32 , NIMBUS 33,34 and XIANSHENG. 35,36 The ligands were prepared using RDKIT 37 and docked into the binding pocket using LEDOCK 38 .…”

Section: Ramd Simulation and Ifps Analysismentioning

confidence: 99%

Deciphering the selectivity of CBL-B inhibitors using all-atom molecular dynamics and machine learning

Zhou,

Du,

et al. 2023

Preprint

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We employ a combination of accelerated molecular dynamics and machine learning techniques to unravel the dynamic characteristics of CBL-B and C-CBL, and how their configurational changes conferring the binding affinity and selectivity of their ligands. We demonstrate that the activity and selectivity against CBL-B and C stem from subtle structural disparities within their binding pockets, and dissociation pathways. Our predictive model for dissociation rate constants (koff) demonstrates a moderate correlation with experimental IC50 values, effectively aligning with two available experimental koff values. Moreover, the binding free energies calculated using MM/GBSA highlight the ΔG distinction between CBL-B and C-CBL. By employing a regression strategy on dissociation trajectories, we identified key amino acids in binding pocket and along the dissociation path responsible for activity and selectivity. These amino acids are statistically significant in achieving activity and selectivity and correspond to the primary structural discrepancies between CBL-B and C-CBL. Through microsecond-scale replica exchange molecular dynamics coupled with generative model of molecular generation and ensemble docking, we accomplish comprehensive simulations of the complete apo-holo-apo transformation cycle. This approach provides an enabling first-in-class drug design technology based on apo-to-holo structure transformation.

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Section: Ramd Simulation and Ifps Analysismentioning

confidence: 99%

Deciphering the selectivity of CBL-B inhibitors using all-atom molecular dynamics and machine learning

Zhou,

Du,

et al. 2023

Preprint

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“…Several small-molecule Cbl-b inhibitors have been reported over the past few years, some of which include compounds 1 – 2 (from Nurix Therapeutics), compound 3 (from Nimbus Therapeutics), and compound 4 (from Hotspot Therapeutics) (Figure ). More recently, Nurix Therapeutics reported an ongoing phase 1 first-in-human clinical trial for advanced solid malignancies with NX-1607 (structure undisclosed), and Hotspot Therapeutics has received an Investigational New Drug (IND) clearance for an allosteric inhibitor of Cbl-b (HST-1011, structure undisclosed)…”

Section: Introductionmentioning

confidence: 99%

Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors

Mfuh,

Boerth,

Bommakanti

et al. 2024

J. Med. Chem.

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Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC 50 value of 30 nM and induces IL-2 production in T-cells with an EC 50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.

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“…Lactams and other nitrogen-containing heterocyclic compounds such as imidazolidinones, oxazolidinones, and imides are important structural units in a large number of natural products and pharmaceuticals. 1–4 In recent years, the selectivity and reactivity of these nitrogen-containing heterocycles as hydrogen atom donors (H-donor), XH, in hydrogen atom transfer reactions (HAT, X–H + Y → X + Y–H) have attracted significant attention from a large number of researchers, gradually becoming a research hotspot. 5–12 Accordingly, it is necessary to develop methods to evaluate the H-donating ability of these nitrogen-containing heterocyclic compounds as H-donors using their characteristic physical parameters.…”

Section: Introductionmentioning

confidence: 99%

Quantitative evaluation of H-donating abilities of C(sp³)–H bonds of nitrogen-containing heterocycles in hydrogen atom transfer reaction

Jia

Shen

et al. 2023

RSC Adv.

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Novel Lactams as Cbl-b Inhibitors for Treating Cancer

Abstract: Provided herein are novel lactams as Cbl-b inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds. Important Compound Classes.

Cited by 5 publications

References 4 publications

Deciphering the selectivity of CBL-B inhibitors using all-atom molecular dynamics and machine learning

Deciphering the selectivity of CBL-B inhibitors using all-atom molecular dynamics and machine learning

Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors

Quantitative evaluation of H-donating abilities of C(sp³)–H bonds of nitrogen-containing heterocycles in hydrogen atom transfer reaction

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Novel Lactams as Cbl-b Inhibitors for Treating Cancer

Abstract: Provided herein are novel lactams as Cbl-b inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds. Important Compound Classes.

Cited by 5 publications

References 4 publications

Deciphering the selectivity of CBL-B inhibitors using all-atom molecular dynamics and machine learning

Deciphering the selectivity of CBL-B inhibitors using all-atom molecular dynamics and machine learning

Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors

Quantitative evaluation of H-donating abilities of C(sp3)–H bonds of nitrogen-containing heterocycles in hydrogen atom transfer reaction

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Quantitative evaluation of H-donating abilities of C(sp³)–H bonds of nitrogen-containing heterocycles in hydrogen atom transfer reaction