靶向难成药蛋白——蛋白质降解剂的力量

Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted,but are of great clinical significance.According to statistics,over 80%of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods.In recent years,with the advancement of basic research and new technologies,the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets.Among them,targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets.This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells.This new form of drug development includes various types such as proteolysis targeting chimera(PROTAC),molecular glue,lysosome-targeting Chimaera(LYTAC),autophagosometethering compound(ATTEC),autophagy-targeting chimera(AUTAC),autophagy-targeting chimera(AUTOTAC),degrader-antibody conjugate(DAC).This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets.Finally,the article looks forward to the future development direction and application prospects of targeted protein degradation technology.

Targeting“undruggable”c-Myc protein by synthetic lethality

Synthetic lethal screening,which exploits the combination of mutations that result in cell death,is a promising method for identifying novel drug targets.This method provides a new avenue for targeting Uundruggable,9 proteins,such as c-Myc.Here,we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network,whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells.We further discuss strategies to identify these functional nodes in the context of synthetic lethality.We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently.

Targeting RAS phosphorylation in cancer therapy:Mechanisms and modulators

RAS,a member of the small GTPase family,functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state.RAS gain-of-function mutations are one of the leading causes in human oncogenesis,accounting for w19%of the global cancer burden.As a well-recognized target in malignancy,RAS has been intensively studied in the past decades.Despite the sustained efforts,many failures occurred in the earlier exploration and resulted in an‘undruggable’feature of RAS proteins.Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins.Therefore,the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties.A better understanding of RAS phosphorylation can contribute to future therapeutic strategies.In this review,we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways.Importantly,the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.

MYC inhibitors in multiple myeloma

The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified.Since then,over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation,especially in hematologic diseases.Indeed,some of the earliest connections among the higher expression of proto-oncogenes(such as MYC),genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma,chronic myeloid leukemia and mouse plasmacytomas.Multiple myeloma(MM),in particular,is a plasma cell malignancy strictly associated with MYC deregulation,suggesting that therapeutic strategies against it would be beneficial in treating this disease.However,targeting MYC was-and,somehow,still is-challenging due to its unique properties:lack of defined three-dimensional structure,nuclear localization and absence of a targetable enzymatic pocket.Despite these difficulties,however,many studies have shown the potential therapeutic impact of direct or indirect MYC inhibition.Different molecules have been tested,in fact,in the context of MM.In this review,we summarize the current status of the different compounds,including the results of their clinical testing,and propose to continue with the efforts to identify,repurpose,redesign or improve drug candidates to combine them with standard of care therapies to overcome resistance and enable better management of myeloma treatment.