Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
2.
Eur J Med Chem ; 247: 115016, 2023 Feb 05.
Article in English | MEDLINE | ID: mdl-36577219

ABSTRACT

CRBN E3 ligase modulators, also anteriorly called immunomodulatory drugs (IMiDs), exhibit excellent pharmacological activity by degrading cereblon (CRBN) associated multiple substrates and have become an important field for drug development. These modulators such as Thalidomide, Lenalidomide and CC-122 abduct CRBN to adhere to IKZF1/3 and other neosubstrates, and then induce the degradation of these substrates, thus retarding the further development of related diseases. Herein, we reported a series of CC-122 derivatives that inhibit the proliferation of hematological malignant tumor cell lines. Studies further confirmed that several derivatives which exhibit strong anti-proliferation effect induce the significant degradation of IKZF1/3. In addition, we found that the best compound 14 (SIAIS355035) exhibits better degradation activity and better anti-proliferation activities than CC-122, especially in diffuse large B lymphoma cell lines. Moreover, the PK properties of compound 14 are pretty promising with excellent oral bioavailability. These results clarified the SAR of CC-122 derivatives preliminarily and suggested that compound 14 has great value for further studies as an ideal novel CRBN E3 ligase modulation drug.


Subject(s)
Peptide Hydrolases , Ubiquitin-Protein Ligases , Ubiquitin-Protein Ligases/metabolism , Peptide Hydrolases/metabolism , Thalidomide , Lenalidomide , Ubiquitination , Transcription Factors/metabolism
3.
Eur J Med Chem ; 244: 114810, 2022 Dec 15.
Article in English | MEDLINE | ID: mdl-36306539

ABSTRACT

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite the great advance in CML treatment through the application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, disease recurrence after TKI discontinuation and clinical resistance mainly due to BCR-ABL mutations continue to be an issue. Herein we report our efforts to synthesize a novel series of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) targeting BCR-ABL based on the allosteric inhibitor asciminib. Our efforts have led to the discovery of compound 30 (SIAIS100) through extensive SAR studies by the optimization of linker parameters as well as linker attachment points of both target-binding warhead and CRBN ligands, which exhibited the most potent degradative activity with a DC50 value of 2.7 nM and Dmax of 91.2% against BCR-ABL and has an IC50 value of 12 nM in BCR-ABL + K562 cells. The binding model and the stability evaluation of 30-induced ternary complex formation were also elucidated through computational simulations. Furthermore, 30 induced sustained and robust BCR-ABL degradation and maintained the efficacy for 96 h post-washout. Moreover, the proteomics analysis showed that 30 degraded BCR-ABL and three CRBN's neo-substrates, including IKZF1, IKZF3, and ZFP91. Additionally, 30 also exerted degradative activity against a panel of clinically relevant resistance-conferring mutations of BCR-ABL, including gatekeeper mutation T315I, several single mutations associated with TKI resistance, and certain highly resistant compound mutations. Our study provided a deeper understanding of the development of PROTACs targeting BCR-ABL and novel potential therapeutic agents for CML treatment.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Humans , Protein Kinase Inhibitors/chemistry , Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , K562 Cells , Mutation , Ubiquitin-Protein Ligases
4.
Chem Commun (Camb) ; 58(72): 10072-10075, 2022 Sep 08.
Article in English | MEDLINE | ID: mdl-35993284

ABSTRACT

By introducing a reactive oxygen species (ROS) triggered leaving group (arylboronic acid) to the parent PROTACs, ROS-responsive Pre-PROTACs were designed and evaluated. Pre-PROTAC (7) efficiently degraded the target protein BRD3 according to ROS levels. Our research provides an effective approach to control PROTAC activation by the endogenous ROS-related microenvironment.


Subject(s)
Neoplasms , Proteolysis , Humans , Neoplasm Proteins , Reactive Oxygen Species , Tumor Microenvironment
5.
Eur J Med Chem ; 223: 113645, 2021 Nov 05.
Article in English | MEDLINE | ID: mdl-34217059

ABSTRACT

Protein degradation is a promising strategy for drug development. Proteolysis-targeting chimeras (PROTACs) hijacking the E3 ligase cereblon (CRBN) exhibit enormous potential and universal degradation performance due to the small molecular weight of CRBN ligands. In this study, the CRBN-recruiting PROTACs were explored on the degradation of oncogenic fusion protein BCR-ABL, which drives the pathogenesis of chronic myeloid leukemia (CML). A series of novel PROTACs were synthesized by conjugating BCR-ABL inhibitor dasatinib to the CRBN ligand including pomalidomide and lenalidomide, and the extensive structure-activity relationship (SAR) studies were performed focusing on optimization of linker parameters. Therein, we uncovered that pomalidomide-based degrader 17 (SIAIS056), possessing sulfur-substituted carbon chain linker, exhibits the most potent degradative activity in vitro and favorable pharmacokinetics in vivo. Besides, degrader 17 also degrades a variety of clinically relevant resistance-conferring mutations of BCR-ABL. Furthermore, degrader 17 induces significant tumor regression against K562 xenograft tumors. Our study indicates that 17 as an efficacious BCR-ABL degrader warrants intensive investigation for the future treatment of BCR-ABL+ leukemia.


Subject(s)
Drug Design , Fusion Proteins, bcr-abl/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Ubiquitin-Protein Ligases/chemistry , Animals , Cell Proliferation/drug effects , Dasatinib/pharmacology , Fusion Proteins, bcr-abl/metabolism , Half-Life , Humans , K562 Cells , Lenalidomide/chemistry , Lenalidomide/metabolism , Ligands , Mice , Neoplasms/drug therapy , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proteolysis , Structure-Activity Relationship , Thalidomide/analogs & derivatives , Thalidomide/chemistry , Thalidomide/metabolism , Transplantation, Heterologous , Ubiquitin-Protein Ligases/metabolism
6.
J Med Chem ; 64(13): 9152-9165, 2021 07 08.
Article in English | MEDLINE | ID: mdl-34138566

ABSTRACT

Proteolysis-targeting chimera (PROTAC) is an attractive technology in drug discovery. Canonically, targets act as a basic starting point in the most previous PROTAC design. Here, we designed degraders considering from the view of clinical benefits. With this novel design, Brigatinib was turned into a degrader SIAIS164018 and endowed with unique features. First, SIAIS164018 could degrade not only ALK fusion proteins in activating or G1202R-mutated form but also mutant EGFR with L858R + T790M, which are two most important targets in non-small-cell lung cancer. Second, SIAIS164018 strongly inhibited cell migration and invasion of Calu-1 and MDA-MB-231. Third and surprisingly, SIAIS164018 degrades several important oncoproteins involved in metastasis such as FAK, PYK2, and PTK6. Interestingly, SIAIS164018 reshuffled the kinome ranking profile when compared to Brigatinib. Finally, SIAIS164018 is orally bioavailable and well tolerated in vivo. SIAIS164018 is an enlightening degrader for us to excavate the charm of protein degradation.


Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Anaplastic Lymphoma Kinase/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Humans , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured
7.
Eur J Med Chem ; 217: 113335, 2021 May 05.
Article in English | MEDLINE | ID: mdl-33751979

ABSTRACT

Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study.


Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Carbazoles/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Discovery , Lung Neoplasms/drug therapy , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Anaplastic Lymphoma Kinase/metabolism , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Biological Availability , Carbazoles/chemistry , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Molecular Structure , Piperidines/chemistry , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship
8.
Org Biomol Chem ; 19(1): 166-170, 2021 01 06.
Article in English | MEDLINE | ID: mdl-33226388

ABSTRACT

As a promising protein degradation strategy, PROTAC technology is increasingly becoming a new star in cancer treatment. Here we report the efficient construction of an IMiD-based azide library via a quick one-step conversion of the existing IMiD-based amine library. This new azide library can act as a kit to endow PROTAC libraries with triazole moieties for various POIs through a highly effective 'click reaction' and then help to rapidly screen out lead degraders that are valuable for drug development. Its power in fleetly identifying potent degraders has been verified on two oncogenic proteins, BCR-ABL and BET, the degraders of which showed comparable potency to or even higher potency than the reported PROTACs in degrading target proteins and effectively inhibiting cancer cell proliferation.

9.
Eur J Med Chem ; 193: 112190, 2020 May 01.
Article in English | MEDLINE | ID: mdl-32179332

ABSTRACT

EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.


Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Development , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Anaplastic Lymphoma Kinase/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , HEK293 Cells , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship
10.
J Med Chem ; 62(20): 9281-9298, 2019 10 24.
Article in English | MEDLINE | ID: mdl-31539241

ABSTRACT

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite great progress for CML treatment through application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, long-term drug administration and clinical resistance continue to be an issue. Herein, we described the design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers. Our efforts have yielded SIAIS178 (19), which induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL+ leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAIS178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL+ leukemia.


Subject(s)
Fusion Proteins, bcr-abl/antagonists & inhibitors , Piperazines/chemistry , Protein Kinase Inhibitors/chemistry , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Animals , Cell Line, Tumor , Cell Survival/drug effects , Drug Design , Drug Evaluation, Preclinical , Fusion Proteins, bcr-abl/metabolism , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Piperazines/metabolism , Piperazines/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Structure-Activity Relationship , Transplantation, Heterologous
SELECTION OF CITATIONS
SEARCH DETAIL
...