Targeted protein degradation is a
promising area in the discovery
and development of innovative therapeutics. Molecular glues mediate
proximity-induced protein degradation and have intrinsic advantages
over heterobifunctional proteolysis-targeting chimeras, including
unprecedented mechanisms, distinct biological activities, and favorable
physicochemical properties. Classical molecular glue degraders have
been identified serendipitously, but rational discovery and design
strategies are emerging rapidly. In this review, we aim to highlight
the recent advances in molecular glues for targeted protein degradation
and discuss the challenges in developing molecular glues into therapeutic
agents. In particular, discovery strategies, action mechanisms, and
representative case studies will be addressed.
Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus . Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.
Natural products
(NPs) are important sources of clinical drugs
due to their structural diversity and biological prevalidation. However,
the structural complexity of NPs leads to synthetic difficulties,
unfavorable pharmacokinetic profiles, and poor drug-likeness. Structural
simplification by truncating unnecessary substructures is a powerful
strategy for overcoming these limitations and improving the efficiency
and success rate of NP-based drug development. Herein, we will provide
a comprehensive review of the structural simplification of NPs with
a focus on design strategies, case studies, and new technologies.
In particular, a number of successful examples leading to marketed
drugs or drug candidates will be discussed in detail to illustrate
how structural simplification is applied in lead optimization of NPs.
Human topoisomerase I (TopoI) is recognized as a valuable target for the development of effective antitumor agents. Structure-based virtual screening was applied to the discovery of structurally diverse TopoI inhibitors. From 23 compounds selected by virtual screening, a total of 14 compounds were found to be TopoI inhibitors. Five hits (compounds 1, 14, 20, 21, and 23) also showed moderate to good in vitro antitumor activity. These novel structures can be considered as good starting points for the development of new antitumor lead compounds. Hit 20 (evodiamine) was chosen for preliminary structure-activity relationship studies. Various groups, including alkyl, benzoyl, benzyl and ester, were introduced to the indole nitrogen atom of evodiamine. The substituted benzoyl groups were found to be favorable for the antitumor activity and spectrum. The 4-Cl benzoyl derivative, compound 29u, was the most active one with IC(50) values in the range 0.049-2.6 μM.
Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using the heterobifunctional PROTAC molecules is generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer‐PROTAC conjugation approach was developed as a novel strategy to improve the tumor‐specific targeting ability and in vivo antitumor potency of conventional PROTACs. As proof of concept, the first aptamer‐PROTAC conjugate (APC) was designed by conjugating a BET‐targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF‐7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor‐specific targeting PROTACs and have broad applications in the development of PROTAC‐based drugs.
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