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1.
J Med Chem ; 67(7): 5275-5304, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38477974

RESUMO

CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC50 ≤ 0.03 nM and Dmax > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3-3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Camundongos , Ratos , Animais , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Proteínas , Proliferação de Células
2.
J Med Chem ; 67(7): 5351-5372, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38530938

RESUMO

CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and are promising cancer therapeutic targets. Herein, we report the discovery of highly potent, selective, and orally bioavailable CBP/p300 degraders using the PROTAC technology with CBPD-409 being the most promising compound. CBPD-409 induces robust CBP/p300 degradation with DC50 0.2-0.4 nM and displays strong antiproliferative effects with IC50 1.2-2.0 nM in the VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. It has a favorable pharmacokinetic profile and achieves 50% of oral bioavailability in mice. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue. CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Animais , Camundongos , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Linhagem Celular Tumoral
3.
J Med Chem ; 66(18): 13280-13303, 2023 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-37683104

RESUMO

We report herein the discovery and extensive characterization of ARD-1676, a highly potent and orally efficacious PROTAC degrader of the androgen receptor (AR). ARD-1676 was designed using a new class of AR ligands and a novel cereblon ligand. It has DC50 values of 0.1 and 1.1 nM in AR+ VCaP and LNCaP cell lines, respectively, and IC50 values of 11.5 and 2.8 nM in VCaP and LNCaP cell lines, respectively. ARD-1676 effectively induces degradation of a broad panel of clinically relevant AR mutants. ARD-1676 has an oral bioavailability of 67, 44, 31, and 99% in mice, rats, dogs, and monkeys, respectively. Oral administration of ARD-1676 effectively reduces the level of AR protein in the VCaP tumor tissue in mice and inhibits tumor growth in the VCaP mouse xenograft tumor model without any sign of toxicity. ARD-1676 is a highly promising development candidate for the treatment of AR+ human prostate cancer.

4.
J Med Chem ; 66(17): 12559-12585, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37647546

RESUMO

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Humanos , Camundongos , Ratos , Animais , Cães , Feminino , Receptor alfa de Estrogênio , Administração Oral , Disponibilidade Biológica , Neoplasias da Mama/tratamento farmacológico
5.
J Med Chem ; 66(13): 8822-8843, 2023 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-37382562

RESUMO

We report the discovery of ARD-2051 as a potent and orally efficacious androgen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051 achieves DC50 values of 0.6 nM and Dmax >90% in inducing AR protein degradation in both the LNCaP and VCaP prostate cancer cell lines, potently and effectively suppresses AR-regulated genes, and inhibits cancer cell growth. ARD-2051 achieves a good oral bioavailability and pharmacokinetic profile in mouse, rat, and dog. A single oral dose of ARD-2051 strongly reduces AR protein and suppresses AR-regulated gene expression in the VCaP xenograft tumor tissue in mice. Oral administration of ARD-2051 effectively inhibits VCaP tumor growth and causes no signs of toxicity in mice. ARD-2051 is a promising AR degrader for advanced preclinical development for the treatment of AR+ human cancers.


Assuntos
Neoplasias da Próstata , Receptores Androgênicos , Masculino , Humanos , Camundongos , Ratos , Animais , Cães , Receptores Androgênicos/metabolismo , Quimera de Direcionamento de Proteólise , Proteólise , Linhagem Celular Tumoral , Neoplasias da Próstata/patologia
6.
J Med Chem ; 66(12): 8222-8237, 2023 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-37289649

RESUMO

Starting from a nonselective bromodomain and extraterminal (BET) inhibitor and a cereblon ligand, we have used precise conformational control for the development of two potent and highly selective BRD4 degraders, BD-7148 and BD-9136. These compounds induce rapid degradation of BRD4 protein in cells at concentrations as low as 1 nM and demonstrate ≥1000-fold degradation selectivity over BRD2 or BRD3 protein. Proteomic analysis of >5700 proteins confirmed their highly selective BRD4 degradation. A single dose of BD-9136 selectively and effectively depletes BRD4 protein in tumor tissues for >48 h. BD-9136 effectively inhibits tumor growth without adverse effects on mice and is more efficacious than the corresponding pan BET inhibitor. This study suggests selective degradation of BRD4 as a strategy for the treatment of human cancers and demonstrates a strategy for the design of highly selective PROTAC degraders.


Assuntos
Neoplasias , Proteínas Nucleares , Humanos , Camundongos , Animais , Proteínas de Ciclo Celular , Fatores de Transcrição , Proteômica
7.
Nat Chem Biol ; 19(6): 703-711, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36732620

RESUMO

Signal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target, but successful targeting of STAT5 has proved to be difficult. Here we report the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. AK-2292 induces degradation of STAT5A/B proteins with an outstanding selectivity over all other STAT proteins and more than 6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and the therapeutic potential of selective STAT5 protein depletion and inhibition but also a promising lead compound toward ultimate development of a STAT5-targeted therapy.


Assuntos
Neoplasias , Fator de Transcrição STAT5 , Humanos , Camundongos , Animais , Fator de Transcrição STAT5/metabolismo
8.
J Med Chem ; 66(4): 2717-2743, 2023 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-36735833

RESUMO

STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity in vivo. We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein in vivo and achieves strong antitumor activity in mice at well-tolerated dose schedules.


Assuntos
Leucemia Mieloide Aguda , Fator de Transcrição STAT5 , Humanos , Animais , Camundongos , Fator de Transcrição STAT5/metabolismo , Ligantes , Leucemia Mieloide Aguda/tratamento farmacológico , Domínios de Homologia de src , Linhagem Celular
9.
Clin Cancer Res ; 28(24): 5455-5468, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36048524

RESUMO

PURPOSE: Development of B-cell lymphoma 2 (BCL-2)-specific inhibitors poses unique challenges in drug design because of BCL-2 homology domain 3 (BH3) shared homology between BCL-2 family members and the shallow surface of their protein-protein interactions. We report herein discovery and extensive preclinical investigation of lisaftoclax (APG-2575). EXPERIMENTAL DESIGN: Computational modeling was used to design "lead" compounds. Biochemical binding, mitochondrial BH3 profiling, and cell-based viability or apoptosis assays were used to determine the selectivity and potency of BCL-2 inhibitor lisaftoclax. The antitumor effects of lisaftoclax were also evaluated in several xenograft models. RESULTS: Lisaftoclax selectively binds BCL-2 (Ki < 0.1 nmol/L), disrupts BCL-2:BIM complexes, and compromises mitochondrial outer membrane potential, culminating in BAX/BAK-dependent, caspase-mediated apoptosis. Lisaftoclax exerted strong antitumor activity in hematologic cancer cell lines and tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia. After lisaftoclax treatment, prodeath proteins BCL-2‒like protein 11 (BIM) and Noxa increased, and BIM translocated from cytosol to mitochondria. Consistent with these apoptotic activities, lisaftoclax entered malignant cells rapidly, reached plateau in 2 hours, and significantly downregulated mitochondrial respiratory function and ATP production. Furthermore, lisaftoclax inhibited tumor growth in xenograft models, correlating with caspase activation, poly (ADP-ribose) polymerase 1 cleavage, and pharmacokinetics of the compound. Lisaftoclax combined with rituximab or bendamustine/rituximab enhanced antitumor activity in vivo. CONCLUSIONS: These findings demonstrate that lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2-selective inhibitor with considerable potential for the treatment of certain hematologic malignancies.


Assuntos
Antineoplásicos , Neoplasias Hematológicas , Proteínas Proto-Oncogênicas c-bcl-2 , Humanos , Antineoplásicos/farmacologia , Apoptose , Proteína 11 Semelhante a Bcl-2 , Caspases , Linhagem Celular Tumoral , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Rituximab/farmacologia
10.
J Med Chem ; 64(19): 14540-14556, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34613724

RESUMO

Embryonic ectoderm development (EED) is a promising therapeutic target for human cancers and other diseases. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded exceptionally potent EED inhibitors. The best compound EEDi-5273 binds to EED with an IC50 value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC50 value of 1.2 nM. It demonstrates an excellent PK and ADME profile, and its oral administration leads to complete and persistent tumor regression in the KARPAS422 xenograft model with no signs of toxicity. Co-crystal structures of two potent EED inhibitors with EED provide a solid structural basis for their high-affinity binding. EEDi-5273 is a promising EED inhibitor for further advanced preclinical development for the treatment of human cancer and other human diseases.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/patologia , Relação Estrutura-Atividade
11.
J Med Chem ; 64(18): 13487-13509, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34473519

RESUMO

We report herein the discovery of exceptionally potent and orally bioavailable PROTAC AR degraders with ARD-2585 being the most promising compound. ARD-2585 achieves DC50 values of ≤0.1 nM in the VCaP cell line with AR gene amplification and in the LNCaP cell line carrying an AR mutation. It potently inhibits cell growth with IC50 values of 1.5 and 16.2 nM in the VCaP and LNCaP cell lines, respectively, and achieves excellent pharmacokinetics and 51% of oral bioavailability in mice. It is more efficacious than enzalutamide in inhibition of VCaP tumor growth and does not cause any sign of toxicity in mice. ARD-2585 is a promising AR degrader for extensive investigations for the treatment of advanced prostate cancer.


Assuntos
Antineoplásicos/uso terapêutico , Ftalimidas/uso terapêutico , Piperidonas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteólise/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/farmacocinética , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Masculino , Camundongos SCID , Estrutura Molecular , Ftalimidas/síntese química , Ftalimidas/farmacocinética , Piperidonas/síntese química , Piperidonas/farmacocinética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Med Chem ; 64(17): 12831-12854, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34431670

RESUMO

Proteolysis targeting chimera (PROTAC) small-molecule degraders have emerged as a promising new type of therapeutic agents, but the design of PROTAC degraders with excellent oral pharmacokinetics is a major challenge. In this study, we present our strategies toward the discovery of highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics. Employing thalidomide to recruit cereblon/cullin 4A E3 ligase and through the rigidification of the linker, we discovered highly potent AR degraders with good oral pharmacokinetic properties in mice with ARD-2128 being the best compound. ARD-2128 achieves 67% oral bioavailability in mice, effectively reduces AR protein and suppresses AR-regulated genes in tumor tissues with oral administration, leading to the effective inhibition of tumor growth in mice without signs of toxicity. This study supports the development of an orally active PROTAC AR degrader for the treatment of prostate cancer and provides insights and guidance into the design of orally active PROTAC degraders.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Administração Oral , Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Descoberta de Drogas , Meia-Vida , Humanos , Injeções Intravenosas , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Med Chem ; 64(14): 10333-10349, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34196551

RESUMO

Targeting the menin-MLL protein-protein interaction is being pursued as a new therapeutic strategy for the treatment of acute leukemia carrying MLL-rearrangements (MLLr leukemia). Herein, we report M-1121, a covalent and orally active inhibitor of the menin-MLL interaction capable of achieving complete and persistent tumor regression. M-1121 establishes covalent interactions with Cysteine 329 located in the MLL binding pocket of menin and potently inhibits growth of acute leukemia cell lines carrying MLL translocations with no activity in cell lines with wild-type MLL. Consistent with the mechanism of action, M-1121 drives dose-dependent down-regulation of HOXA9 and MEIS1 gene expression in the MLL-rearranged MV4;11 leukemia cell line. M-1121 is orally bioavailable and shows potent antitumor activity in vivo with tumor regressions observed at tolerated doses in the MV4;11 subcutaneous and disseminated models of MLL-rearranged leukemia. Together, our findings support development of an orally active covalent menin inhibitor as a new therapy for MLLr leukemia.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas/metabolismo , Relação Estrutura-Atividade
14.
ACS Med Chem Lett ; 12(6): 996-1004, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34141084

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. We report herein our extensive in vitro and in vivo evaluations of SD-91, the product of the hydrolysis of our previously reported STAT3 degrader SD-36. SD-91 binds to STAT3 protein with a high affinity and displays >300-fold selectivity over other STAT family protein members. SD-91 potently and effectively induces degradation of STAT3 protein and displays a high selectivity over other STAT members and >7000 non-STAT proteins in cells. A single administration of SD-91 selectively depletes STAT3 protein in tumor tissues with a persistent effect. SD-91 achieves complete and long-lasting tumor regression in the MOLM-16 xenograft model in mice even with weekly administration. Hence, SD-91 is a potent, highly selective, and efficacious STAT3 degrader for extensive evaluations for the treatment of human cancers and other diseases for which STAT3 plays a key role.

15.
J Med Chem ; 63(22): 13994-14016, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33185101

RESUMO

We report herein the discovery of a class of potent small-molecule inhibitors of anaplastic lymphoma kinase (ALK) containing a fused indoloquinoline scaffold. The most promising compound CJ-2360 has an IC50 value of 2.2 nM against wild-type ALK and low-nanomolar potency against several clinically reported ALK mutants. This compound is capable of achieving complete tumor regression in the ALK-positive KARPAS-299 xenograft model with oral administration in mice. CJ-2360 represents a promising ALK inhibitor for advanced preclinical development.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Descoberta de Drogas , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/patologia , Camundongos , Camundongos SCID , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Neoplasia ; 22(10): 522-532, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32928363

RESUMO

The androgen receptor (AR) has been found to be expressed in the majority of human breast cancer and AR antagonists, such as enzalutamide, have shown promising clinical activity in AR-positive (AR+) breast cancer. We have recently reported the discovery of a highly potent PROTAC AR degrader, ARD-61. In this study, we evaluated ARD-61 for its therapeutic potential and mechanism of action in breast cancer models in vitro and in vivo. ARD-61 potently and effectively induces AR degradation in AR+ breast cancer cell lines and is much more potent than enzalutamide in inhibition of cell growth and induction of cell cycle arrest and/or apoptosis. ARD-61 effectively induces complete AR degradation in xenograft tumor tissue and is more effective than enzalutamide in achieving tumor growth inhibition in the MDA-MB-453 xenograft model in mice. Our study provides strong preclinical rationale to develop AR degraders for the treatment of AR+ human breast cancer.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Piperidinas/farmacologia , Proteólise , Pirrolidinas/farmacologia , Receptores Androgênicos/química , Tiazóis/farmacologia , Animais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular , Movimento Celular , Proliferação de Células , Feminino , Humanos , Técnicas In Vitro , Camundongos , Camundongos SCID , Piperidinas/uso terapêutico , Pirrolidinas/uso terapêutico , Tiazóis/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Med Chem ; 63(13): 7252-7267, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32580550

RESUMO

Inhibition of embryonic ectoderm development (EED) is a new cancer therapeutic strategy. Herein, we report our discovery of EEDi-5285 as an exceptionally potent, efficacious, and orally active EED inhibitor. EEDi-5285 binds to the EED protein with an IC50 value of 0.2 nM and inhibits cell growth with IC50 values of 20 pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively, carrying an EZH2 mutation. EEDi-5285 is approximately 100 times more potent than EED226 in binding to EED and >300 times more potent than EED226 in inhibition of cell growth in the KARPAS422 cell line. EEDi-5285 has excellent pharmacokinetics and achieves complete and durable tumor regression in the KARPAS422 xenograft model in mice with oral administration. The cocrystal structure of EEDi-5285 in a complex with EED defines the precise structural basis for their high binding affinity. EEDi-5285 is the most potent and efficacious EED inhibitor reported to date.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexo Repressor Polycomb 2/antagonistas & inibidores , Complexo Repressor Polycomb 2/química , Bibliotecas de Moléculas Pequenas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Histonas/metabolismo , Humanos , Linfoma/tratamento farmacológico , Linfoma/patologia , Camundongos SCID , Complexo Repressor Polycomb 2/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Med Chem ; 63(9): 4997-5010, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32338903

RESUMO

Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (16) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.


Assuntos
Antineoplásicos/uso terapêutico , Azetidinas/uso terapêutico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Azetidinas/síntese química , Azetidinas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos SCID , Estrutura Molecular , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Med Chem ; 62(24): 11280-11300, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31747516

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and an attractive therapeutic target for cancer and other human diseases. Despite 20 years of persistent research efforts, targeting STAT3 has been very challenging. We report herein the structure-based discovery of potent small-molecule STAT3 degraders based upon the proteolysis targeting chimera (PROTAC) concept. We first designed SI-109 as a potent, small-molecule inhibitor of the STAT3 SH2 domain. Employing ligands for cereblon/cullin 4A E3 ligase and SI-109, we obtained a series of potent PROTAC STAT3 degraders, exemplified by SD-36. SD-36 induces rapid STAT3 degradation at low nanomolar concentrations in cells and fails to degrade other STAT proteins. SD-36 achieves nanomolar cell growth inhibitory activity in leukemia and lymphoma cell lines with high levels of phosphorylated STAT3. A single dose of SD-36 results in complete STAT3 protein degradation in xenograft tumor tissue and normal mouse tissues. SD-36 achieves complete and long-lasting tumor regression in the Molm-16 xenograft tumor model at well-tolerated dose-schedules. SD-36 is a potent, selective, and efficacious STAT3 degrader.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azocinas/química , Desenho de Fármacos , Descoberta de Drogas , Indóis/química , Indóis/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Organofosfonatos/química , Proteólise/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/farmacocinética , Apoptose , Azocinas/farmacocinética , Azocinas/farmacologia , Proliferação de Células , Feminino , Humanos , Indóis/farmacocinética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos SCID , Estrutura Molecular , Organofosfonatos/farmacocinética , Organofosfonatos/farmacologia , Conformação Proteica , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/química , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cancer Cell ; 36(5): 498-511.e17, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31715132

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Camundongos , Proteólise/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
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