(LGH-447) - 药物靶点：PIM1 x PIM2 x PIM3_在研适应症：多发性骨髓瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

PIM1 x PIM2 x PIM3

作用机制

PIM1抑制剂(Pim-1 激酶抑制剂)、PIM2抑制剂(Pim-2 激酶抑制剂)、PIM3抑制剂(Pim-3 激酶抑制剂)

治疗领域

肿瘤免疫系统疾病心血管疾病+ [1]

在研适应症

多发性骨髓瘤

非在研适应症

急性髓性白血病骨髓增生异常综合征骨髓纤维化+ [3]

原研机构

Novartis Pharma AG

在研机构

Novartis Pharma AG

非在研机构

Novartis Pharmaceuticals Corp.

Novartis Oncology, Inc.

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C24H23F3N4O

InChIKeyVRQXRVAKPDCRCI-ZNMIVQPWSA-N

CAS号1210608-43-7

关联

9

项与 LGH-447 相关的临床试验

NCT02370706 / Completed临床1期

A Phase Ib, Multi-center, Open-label, Dose-escalation Study of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 Administered Orally in Patients With Myelofibrosis

This is a phase Ib study with the primary purpose is to estimate the MTD and/or RDE for the triple combination of PIM447, formerly LGH447, plus ruxolitinib and LEE011 as well as for the doublets, PIM447 plus ruxolitinib, and LEE011 plus ruxolitinib, in patients with myelofibrosis (MF). Each regimen will be assessed for safety, tolerability, pharmacokinetics (PK) and pharmacodynamic effects, and preliminary anti-myelofibrosis activity, including changes in spleen volume, JAK2V617F allele burden, and hematologic response.

开始日期2015-05-21

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT02160951 / Completed临床1期

A Multi-center, Open-label, Dose Escalation, Phase 1 Study of Oral LGH447 in Japanese Patients With Relapsed and/or Refractory Hematologic Malignancies

This is a multi-center, open-label, dose escalation, Phase 1 study of oral LGH447 in Japanese patients with relapsed and/or refractory multiple myeloma for which no standard effective treatment options exist.
The study consists of a dose escalation part to estimate the maximum tolerated dose and/or the recommended dose for expansion and a dose expansion part to further assess safety and preliminary anti-cancer activity of LGH447 at the maximum tolerated dose and/or the recommended dose for expansion.

开始日期2014-09-01

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT02144038 / Completed临床1期

A Phase Ib/II, Multi-center, Study of Oral LGH447 in Combination With Oral BYL719 in Patients With Relapsed and Refractory Multiple Myeloma

This is a Phase Ib/II study with the primary purpose of the Phase Ib part being to estimate the MTD and/or recommended phase 2 dose (RP2D) of the combination of LGH447 and BYL719 when administered orally to adult patients with relapsed and refractory multiple myeloma. Once the MTD and/or RP2D is determined for the combination of LGH447 and BYL719, additional patients will be enrolled in the Phase II part to determine whether the combination of LGH447 and BYL719 exhibits improved anti-multiple myeloma activity compared to single agent LGH447. This trial never made it to the Phase II part of the this trial.

开始日期2014-07-23

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 LGH-447 相关的临床结果

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100 项与 LGH-447 相关的转化医学

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100 项与 LGH-447 相关的专利（医药）

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18

项与 LGH-447 相关的文献（医药）

2021-06-15·Clinical Cancer Research1区 · 医学

Therapeutic Efficacy of Combined JAK1/2, Pan-PIM, and CDK4/6 Inhibition in Myeloproliferative Neoplasms

1区 · 医学

Article

作者: Derkach, Andriy ; Vanasse, Gary ; Longmire, Tyler ; Rong, Xianhui ; Li, Bing ; Krishnan, Aishwarya ; Cao, Zhu A. ; Rampal, Raajit K. ; Spitzer, Barbara ; Mowla, Shoron ; Eisman, Shira Esther ; Devlin, Sean ; An, Wenbin ; Koche, Richard ; Cordner, Keith ; Durham, Benjamin ; Somasundara, Amritha Varshini Hanasoge ; Levine, Ross L. ; Pinzon-Ortiz, Maria ; Whitfield, Justin T.

AbstractPurpose:The JAK1/2 inhibitor ruxolitinib has demonstrated significant benefits for patients with myeloproliferative neoplasms (MPN). However, patients often lose response to ruxolitinib or suffer disease progression despite therapy with ruxolitinib. These observations have prompted efforts to devise treatment strategies to improve therapeutic efficacy in combination with ruxolitinib therapy. Activation of JAK–STAT signaling results in dysregulation of key downstream pathways, notably increased expression of cell-cycle mediators including CDC25A and the PIM kinases.Experimental Design:Given the involvement of cell-cycle mediators in MPNs, we sought to examine the efficacy of therapy combining ruxolitinib with a CDK4/6 inhibitor (LEE011) and a PIM kinase inhibitor (PIM447). We utilized JAK2-mutant cell lines, murine models, and primary MPN patient samples for these studies.Results:Exposure of JAK2-mutant cell lines to the triple combination of ruxolitinib, LEE011, and PIM447 resulted in expected on-target pharmacodynamic effects, as well as increased apoptosis and a decrease in the proportion of cells in S-phase, compared with ruxolitinib. As compared with ruxolitinib monotherapy, combination therapy led to reductions in spleen and liver size, reduction of bone marrow reticulin fibrosis, improved overall survival, and elimination of disease-initiating capacity of treated bone marrow, in murine models of MPN. Finally, the triple combination reduced colony formation capacity of primary MPN patient samples to a greater extent than ruxolitinib.Conclusions:The triple combination of ruxolitinib, LEE011, and PIM447 represents a promising therapeutic strategy with the potential to increase therapeutic responses in patients with MPN.

2021-06-01·International Journal of Hematology4区 · 医学

A phase I, dose-escalation study of oral PIM447 in Japanese patients with relapsed and/or refractory multiple myeloma

4区 · 医学

Article

作者: Iida, Shinsuke ; Rinne, Mikael ; Taniwaki, Masafumi ; Minami, Hironobu ; Hatake, Kiyohiko ; Natsume, Kazuto ; Sunami, Kazutaka ; Sekiguchi, Risa ; Ishikawa, Norifumi

PIM447, a pan-proviral integration site for Moloney leukemia (PIM) kinase inhibitor, has shown preclinical activity in multiple myeloma (MM). This phase I, open-label, multicenter, dose-escalation study aimed to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of PIM447 in Japanese patients with relapsed and/or refractory (R/R) MM. The study included 13 patients (250 mg once daily (QD), [n = 7]; 300 mg QD, [n = 6]). The sole dose-limiting toxicity observed was grade 3 QTc prolongation in one patient from the 300 mg group, and the MTD and RDE was not determined. The most common suspected PIM447-related adverse events (AEs) included thrombocytopenia (76.9%), anemia (53.8%), and leukopenia (53.8%). All patients experienced at least one grade 3 or 4 AE, most frequently thrombocytopenia or leukopenia (61.5% each). The overall response rate was 15.4%, disease control rate 69.2%, clinical benefit rate 23.1%, and two patients had a partial response (one in each dose group). Two patients treated with 250 mg QD had a progression-free survival > 6 months. PIM447 250 mg or 300 mg QD was tolerated in Japanese patients with R/R MM. Further studies are required to evaluate clinical outcomes of PIM447 in combination with other drugs for the treatment of MM.Trial registration: clinicaltrials.gov: (NCT02160951).

2021-06-01·Journal of Pediatric Surgery3区 · 医学

PIM447 inhibits oncogenesis and potentiates cisplatin effects in hepatoblastoma

3区 · 医学

Article

作者: Stewart, Jerry E ; Aye, Jamie M ; Quinn, Colin H ; Yoon, Karina J ; Marayati, Raoud ; Markert, Hooper R ; Wadhwani, Nikita ; Beierle, Elizabeth A ; Bownes, Laura V

BACKGROUNDNovel therapies are needed for patients with hepatoblastoma because of an increasing incidence of disease and poor prognosis for advanced, refractory, and recurrent disease. PIM kinases promote tumorigenesis in hepatoblastoma. A novel PIM inhibitor, PIM447, has shown promise in inhibiting oncogenesis in hematologic and lymphoid malignancies. We hypothesized that PIM inhibition with PIM447 would result in decreased tumorigenesis in hepatoblastoma.METHODSThe effects of PIM447 on hepatoblastoma viability, proliferation, motility, apoptosis, and tumor cell stemness were assessed in HuH6, a human hepatoblastoma cell line, and COA67, a human hepatoblastoma patient-derived xenograft.RESULTSPIM447 significantly decreased the viability, proliferation, and motility of HuH6 and COA67 cells. Apoptosis significantly increased following PIM447 treatment. PIM447 had a significant impact on tumor cell stemness as evidenced by decreased expression of CD133 and reduced ability of HuH6 and COA67 cells to form tumorspheres. Furthermore, combining PIM447 with cisplatin resulted in a significant decrease in cell viability compared to either treatment alone.CONCLUSIONWe showed that PIM447 inhibits oncogenesis and potentiates the effects of cisplatin in hepatoblastoma and, therefore, warrants further investigation as a potential therapeutic agent for hepatoblastoma.

100 项与 LGH-447 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14943

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
复发性多发性骨髓瘤	临床3期	新加坡	Novartis Pharmaceuticals Corp.	2012-04-25
复发性多发性骨髓瘤	临床3期	美国	Novartis Pharmaceuticals Corp.	2012-04-25
复发性多发性骨髓瘤	临床3期	西班牙	Novartis Pharmaceuticals Corp.	2012-04-25
复发性多发性骨髓瘤	临床3期	德国	Novartis Pharmaceuticals Corp.	2012-04-25
骨髓增生异常综合征	临床3期	意大利	Novartis Oncology, Inc.	-
浆细胞骨髓瘤难治	临床2期	德国	Novartis Pharmaceuticals Corp.	2012-04-25
浆细胞骨髓瘤难治	临床2期	美国	Novartis Pharmaceuticals Corp.	2012-04-25
多发性骨髓瘤	临床2期	-	Novartis Pharma AG	-
骨髓增生异常综合征	临床前	日本	Novartis Oncology, Inc.	-
骨髓增生异常综合征	临床前	德国	Novartis Oncology, Inc.	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


EHA2023	N/A	急性红细胞白血病	-	PIM447	艱衊範顧鹽衊齋蓋艱餘(蓋繭齋願襯網築觸襯築) = 繭鑰構鬱網顧遞鏇壓願廠顧鹽廠鹹壓壓鏇糧觸 (網鑰醖醖齋觸遞鏇選觸 )	-	2023-06-08
Pubmed \| Leukemia 人工标引	临床1期	多发性骨髓瘤	79	PIM447	(鹹繭鹹繭顧廠廠廠鹽窪) = 餘顧襯醖壓獵夢遞鹽艱網築積鹹廠衊鹽鹹選願 (網鹽鬱廠遞築遞網夢鏇 ) 更多	积极	2019-12-01
NCT02160951 (Pubmed \| Int J Hematol) 人工标引	临床1期	多发性骨髓瘤	13	PIM 447	(糧衊廠衊觸積築襯艱廠) = grade 3 QTc prolongation in one patient from the 300 mg group 選構蓋鬱艱夢簾襯鹽觸 (壓襯選鹽蓋簾憲鏇蓋願 ) 更多	积极	2021-06-01
EHA2023	N/A	髓系白血病	-	PIM447	鹽廠範蓋衊顧淵窪淵簾(顧淵製積憲鹹淵觸壓範) = 醖鏇膚選網艱繭齋襯鹽鹽鹹範範壓糧鑰鹽築鬱 (積獵鹽築壓蓋艱壓鬱衊 ) 更多	-	2023-06-08