scholarly journals Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers

2021 ◽  
Vol 22 (22) ◽  
pp. 12142
Author(s):  
Soonsil Hyun ◽  
Dongyun Shin
Keyword(s):  
Drug Resistance ◽  
Cancer Treatment ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Ras Gene ◽  
Tumor Patients ◽  
Kras Mutations ◽  
Ras Pathway ◽  
Ras Protein ◽  
Potential Applications

Drug resistance continues to be a major problem associated with cancer treatment. One of the primary causes of anticancer drug resistance is the frequently mutated RAS gene. In particular, considerable efforts have been made to treat KRAS-induced cancers by directly and indirectly controlling the activity of KRAS. However, the RAS protein is still one of the most prominent targets for drugs in cancer treatment. Recently, novel targeted protein degradation (TPD) strategies, such as proteolysis-targeting chimeras, have been developed to render “undruggable” targets druggable and overcome drug resistance and mutation problems. In this study, we discuss small-molecule inhibitors, TPD-based small-molecule chemicals for targeting RAS pathway proteins, and their potential applications for treating KRAS-mutant cancers. Novel TPD strategies are expected to serve as promising therapeutic methods for treating tumor patients with KRAS mutations.

Small-molecule degraders of cyclin-dependent kinase protein: a review

2021 ◽  
Author(s):  
Bin Yu ◽  
Zekun Du ◽  
Yuming Zhang ◽  
Zhiyu Li ◽  
Jinlei Bian
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Protein Degradation ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Structural Characteristics ◽  
Protein A ◽  
Cyclin Dependent Kinase ◽  
Chemical Tools ◽  
Potential Therapeutics

Proteolysis-targeting chimeras are a new modality of chemical tools and potential therapeutics involving the induction of protein degradation. Cyclin-dependent kinase (CDK) protein, which is involved in cycles and transcription cycles, participates in regulation of the cell cycle, transcription and splicing. Proteolysis-targeting chimeras targeting CDKs show several advantages over traditional CDK small-molecule inhibitors in potency, selectivity and drug resistance. In addition, the discovery of molecule glues promotes the development of CDK degraders. Herein, the authors describe the existing CDK degraders and focus on the discussion of the structural characteristics and design of these degraders.

Abstract 3516: Discovery of novel SHMT small molecule inhibitors for cancer treatment

2018 ◽  
Author(s):  
Anna Bartosik ◽  
Pawel Guzik ◽  
Marta Sowinska ◽  
Karolina Gluza ◽  
Marcin Krol ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Small Molecule ◽  
Small Molecule Inhibitors

Computational and Biological Investigations on Abl1 Tyrosine Kinase: A Review

2020 ◽  
Vol 22 (1) ◽  
pp. 38-51
Author(s):  
Masilamani Elizabeth Sobhia ◽  
G. Siva Kumar ◽  
Antara Mallick ◽  
Harmanpreet Singh ◽  
Kranthi Kumar ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Small Molecule Inhibitors ◽  
Valuable Insight ◽  
Term Survival ◽  
Biological Studies

: Abl1 tyrosine kinase is a validated target for the treatment of chronic myeloid leukemia. It is a form of cancer that is difficult to treat and much research is being done to identify new molecular entities and to tackle drug resistance is-sues. In recent years, drug resistance of Abl1 tyrosine kinase has become a major healthcare concern. Second and third generation TKI reported better responses against the resistant forms, still they had no impact on long term survival pro-longation. New compounds derived from natural products and organic small molecule inhibitors can lay the foundation for better clinical therapies in the future. Computational methods, experimental and biological studies can help us under-stand the mechanism of drug resistance and identify novel molecule inhibitors. ADMET parameters analysis of reported drugs and novel small molecule inhibitors can also provide valuable insight. In this review, available therapies, point mu-tations, structure-activity relationship and ADMET parameters of reported series of Abl1 tyrosine kinase inhibitors and drugs are summarised. We summarise in detail recent computational and molecular biology studies that focus on design-ing drug molecules, investigation of natural product compounds and organic new chemical entities. Current ongoing re-search suggests that selective targeting of Abl1 tyrosine kinase at the molecular level to combat drug resistance in chronic myeloid leukemia is promising.

scholarly journals ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors—A STING in the Tale of ENPP1

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4192 ◽  
Author(s):  
Kenneth I. Onyedibe ◽  
Modi Wang ◽  
Herman O. Sintim
Keyword(s):  
Small Molecule ◽  
Cyclic Gmp ◽  
Small Molecule Inhibitors ◽  
Purinergic Signaling ◽  
Type Ii ◽  
Disease States ◽  
Transmembrane Glycoprotein ◽  
Nucleotide Pyrophosphatase ◽  
Potential Applications

Ectonucleotide pyrophosphatase/phosphodiesterase I (ENPP1) was identified several decades ago as a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activities, critical for purinergic signaling. Recently, ENPP1 has emerged as a critical phosphodiesterase that degrades the stimulator of interferon genes (STING) ligand, cyclic GMP–AMP (cGAMP). cGAMP or analogs thereof have emerged as potent immunostimulatory agents, which have potential applications in immunotherapy. This emerging role of ENPP1 has placed this “old” enzyme at the frontier of immunotherapy. This review highlights the roles played by ENPP1, the mechanism of cGAMP hydrolysis by ENPP1, and small molecule inhibitors of ENPP1 with potential applications in diverse disease states, including cancer.

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