RESUMO
Discoidin domain receptor 1 (DDR1) is a potential target for cancer drug discovery. Although several DDR1 kinase inhibitors have been developed, recent studies have revealed the critical roles of the noncatalytic functions of DDR1 in tumor progression, metastasis, and immune exclusion. Degradation of DDR1 presents an opportunity to block its noncatalytic functions. Here, we report the discovery of the DDR1 degrader LLC355 by employing autophagosome-tethering compound technology. Compound LLC355 efficiently degraded DDR1 protein with a DC50 value of 150.8 nM in non-small cell lung cancer NCI-H23 cells. Mechanistic studies revealed compound LLC355 to induce DDR1 degradation via lysosome-mediated autophagy. Importantly, compound LLC355 potently suppressed cancer cell tumorigenicity, migration, and invasion and significantly outperformed the corresponding inhibitor 1. These results underline the therapeutic advantage of targeting the noncatalytic function of DDR1 over inhibition of its kinase activity.
Assuntos
Autofagia , Receptor com Domínio Discoidina 1 , Humanos , Receptor com Domínio Discoidina 1/metabolismo , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Descoberta de Drogas , Movimento Celular/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Relação Estrutura-Atividade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Proliferação de Células/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismoRESUMO
Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC50 value of 20 nM and a Dmax value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo.
Assuntos
Histona-Lisina N-Metiltransferase , Proteólise , Humanos , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Camundongos , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Descoberta de Drogas , Complexo de Endopeptidases do Proteassoma/metabolismo , Relação Estrutura-Atividade , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Histonas/metabolismo , Proliferação de Células/efeitos dos fármacosRESUMO
The androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to drive hyper-proliferative, metastatic, or therapy-resistant phenotypes, the molecular mechanisms of which remain poorly understood. Here, we show that the tumor-specific enhancer circuitry of AR is critically reliant on the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone 3 lysine 36 di-methyltransferase. NSD2 expression is abnormally gained in prostate cancer cells and its functional inhibition impairs AR trans-activation potential through partial off-loading from over 40,000 genomic sites, which is greater than 65% of the AR tumor cistrome. The NSD2-dependent AR sites distinctly harbor a chimeric AR-half motif juxtaposed to a FOXA1 element. Similar chimeric motifs of AR are absent at the NSD2-independent AR enhancers and instead contain the canonical palindromic motifs. Meta-analyses of AR cistromes from patient tumors uncovered chimeric AR motifs to exclusively participate in tumor-specific enhancer circuitries, with a minimal role in the physiological activity of AR. Accordingly, NSD2 inactivation attenuated hallmark cancer phenotypes that were fully reinstated upon exogenous NSD2 re-expression. Inactivation of NSD2 also engendered increased dependency on its paralog NSD1, which independently maintained AR and MYC hyper-transcriptional programs in cancer cells. Concordantly, a dual NSD1/2 PROTAC degrader, called LLC0150, was preferentially cytotoxic in AR-dependent prostate cancer as well as NSD2-altered hematologic malignancies. Altogether, we identify NSD2 as a novel subunit of the AR neo-enhanceosome that wires prostate cancer gene expression programs, positioning NSD1/2 as viable paralog co-targets in advanced prostate cancer.