Delving into the Latest Updates on PT-2385 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

HIF-2α

Mechanism

HIF-2α inhibitors(Endothelial PAS domain-containing protein 1 inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesCardiovascular Diseases+ [4]

Active Indication

Renal Cell CarcinomaVon Hippel-Lindau DiseaseLocally Advanced Clear Cell Renal Cell Carcinoma

Inactive Indication

Recurrent Glioblastoma

Originator Organization

Peloton Therapeutics, Inc.

Active Organization

Peloton Therapeutics, Inc.

The University of Texas Southwestern Medical Center

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC17H12F3NO4S

InChIKeyONBSHRSJOPSEGS-INIZCTEOSA-N

CAS Registry1672665-49-4

This is an exploratory study to assess [18F]PT2385 Positron Emission Tomography/Computed Tomography (PET/CT) in patients with renal cell carcinoma (RCC). This is an open-label, nontherapeutic trial. The main objective is to correlate hypoxia-inducible factor-2alpha (HIF2α) levels as determined by an investigational [18F]PT2385 PET/CT scan with the levels on subsequently obtained tissue by HIF2α immunohistochemistry (IHC). There will be three cohorts. The first pre-surgical cohort will have [18F]PT2385 PET/CT prior to nephrectomy. The uptake and retention on Positron Emission Tomography (PET), quantified as standardized uptake value (SUV) max and mean, abbreviated SUV henceforth will be correlated with HIF2α levels by IHC on the primary tumor. The second cohort will comprise patients with metastatic clear cell renal carcinoma (ccRCC). SUV will be correlated with HIF2α levels measured by IHC on a biopsy sample from a metastasis. Both low- and high-avidity sites will be biopsied and tracer uptake correlated with HIF2α IHC. A third cohort will include patients with Von Hippel-Lindau (VHL) syndrome and any of the following disease manifestations - RCC, central nervous system (CNS) hemangioblastoma, and/or pancreatic neuroendocrine tumor(s). Investigational imaging will evaluate HIF2α expression within a tumor type and across different tumor types. A biopsy is encouraged but not mandatory for this cohort.

Start Date18 Aug 2021

Sponsor / Collaborator

The University of Texas Southwestern Medical Center

NCT03216499 / CompletedPhase 2IIT

Single-Arm, Open-Label Phase II Efficacy Study of First-in-Class HIF-2 Alpha Inhibitor, PT2385, for Patients With Recurrent Glioblastoma

This phase II trial studies how well HIF-2 alpha inhibitor PT2385 works in treating patients with recurrent glioblastoma. HIF-2 alpha inhibitor PT2385 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Start Date14 Sep 2017

Sponsor / Collaborator

The Sidney Kimmel Comprehensive Cancer Center

[+2]

NCT03108066 / CompletedPhase 2

An Open Label Phase 2 Study to Evaluate PT2385 for the Treatment of Von Hippel-Lindau Disease-Associated Clear Cell Renal Cell Carcinoma

The primary objective of this study is to assess the overall response rate (ORR) of von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC) tumors in VHL participants treated with MK-3795.

Start Date24 Apr 2017

Sponsor / Collaborator

Peloton Therapeutics, Inc.

[+1]

100 Clinical Results associated with PT-2385

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100 Translational Medicine associated with PT-2385

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100 Patents (Medical) associated with PT-2385

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45

Literatures (Medical) associated with PT-2385

01 Dec 2024·International Journal of Pharmaceutics

A pH-responsive novel delivery system utilizing carbon quantum dots loaded with PT2385 for targeted inhibition of HIF-2α in the treatment of osteoarthritis

Article

Author: Liu, Yang ; Wu, Gai-Ge ; Wang, Shao-Wei ; Liu, Meng-Rou ; Li, Peng-Cui ; Wei, Xiao-Chun ; Zhang, Cheng-Ming ; Kang, Yu-Xin ; Duan, Qian-Qian ; Zhao, Rui-Peng ; Guo, Li ; Zheng, Si-Yu

BACKGROUNDOsteoarthritis (OA) is a progressive joint disorder marked by the degradation of cartilage. Elevated concentrations of hypoxia-inducible factor-2α (HIF-2α) are intricately linked to the pathological development of OA. PT2385 has demonstrated effective inhibition of HIF-2α, thereby potentially impeding the initial advancement of OA. Nevertheless, challenges persist, including limited penetration into the deeper layers of cartilage, issues related to charge rejection, and a heightened rate of clearance from the joint. These constraints necessitate further consideration and exploration.METHODSIt has been demonstrated that PT2385 exhibits efficient inhibition of HIF-2α expression, thereby contributing to the delay in the progression of osteoarthritis. The pH-responsive attributes of carbon quantum dots, specifically those employing m-phenylenediamine (m-CQDs) coated with bovine serum albumin (BSA), have been systematically evaluated. In both in vitro settings involving cartilage explants and in vivo experiments, the efficacy of BSA-m-CQDs-PT2385 (BCP) has been confirmed in facilitating the transport of PT2385 to the middle and deep layers of cartilage. Furthermore, the BCP system demonstrates controlled drug release contingent upon alterations in environmental pH.RESULTSWhile the use of PT2385 alone provides protective effects on chondrocytes within an inflamed environment, there exists an opportunity for further enhancement in its efficacy when administered via intra-articular injection. The BCP formulation, characterized by appropriate particle size and charge, facilitates seamless penetration into cartilage tissue. Additionally, BCP demonstrates the capability to release drugs in response to changes in environmental pH. In vitro experiments reveal that BCP effectively inhibits Hif-2α expression and catabolic factors in chondrocytes. Notably, cartilage explants and in vivo experiments indicate that BCP surpasses PT2385 alone in inhibiting the expression of HIF-2α and matrix metalloproteinase 13, particularly in the middle and deep layers.CONCLUSIONSThe BCP drug delivery system exhibits selective release of PT2385 in response to pH changes occurring during the progression of osteoarthritis (OA), thereby inhibiting HIF-2α expression deep within the cartilage. The use of BCP significantly augments the capacity of PT2385 to retard both cartilage degeneration and the progression of osteoarthritis. Consequently, BCP as an innovative approach utilizing m-CQDs to deliver PT2385 into articular cartilage, shows potential for treating osteoarthritis.This strategy opens new avenues for osteoarthritis treatment.

01 Nov 2024·Biochemical Pharmacology

The ‘ABC’ of split-nanoluciferase HIF heterodimerization bioassays: Applications, Benefits & Considerations

Article

Author: Janssens, Liesl K ; Stove, Christophe P

Hypoxia-inducible factors (HIF) are interesting targets for multiple therapeutic indications. While HIF activation is desired for the treatment of anemia-related and ischemic diseases, HIF inhibition is of tremendous interest to anti-cancer drug development. Different signaling events within the HIF pathway are being targeted by drug discovery programs, with a special interest in HIF-selective (possibly also HIF1/2 isoform-selective) compounds. In this study, we applied recently developed cell-based split-nanoluciferase HIF heterodimerization assays to study the effects of compounds, targeting HIF activity by various mechanisms of action. This study shows that the application of similar or diverse assay protocols allows to detect various influences on HIF heterodimerization as a key signaling event in the oxygen sensing pathway: increased HIF heterodimerization (roxadustat, MG-132), decreased HIF heterodimerization (PX-478, ibuprofen) and direct (HIF isoform-selective) heterodimerization inhibiting effects (PT-2385). Changes in treatment time and in the assay protocol allowed to assess direct and indirect effects on HIFα-HIFβ heterodimerization. In addition to the evaluation of applications of these new bioassays regarding pharmacological characterizations, benefits and considerations are discussed related to the use of cellular, luminescent-based bioassays. Briefly, benefits include the bidirectional nature of the biological readout, the upstream mechanism of detection, the differentiation between HIF1 and HIF2 effects and the simulation of various conditions. Specific and general considerations include cell-based, technical and disease/drug-related aspects (e.g., non-specific effects, color interference). In summary, the versatility of these bioassays offers benefits in widespread applications regarding drug discovery and pharmacological characterization of various therapeutics, applying either the same or optimized experimental protocols.

01 Oct 2024·European Journal of Pharmaceutical Sciences

Ameliorating effects of the HIF-2α inhibitor PT2385 on high-altitude polycythemia

Article

Author: Luobu, Gesang ; Li, Kang ; Ciren, Dawa ; Li, Ka ; Li, Qijie ; Xiao, Xue ; Wu, Ping

High-altitude polycythemia (HAPC) is a common chronic altitude disease caused by living in low-pressure and low-oxygen environment. At present, there is still no effective cure for HAPC. HIF-2α may play an important role in the development of HAPC in regulating the increased red blood cell excessively induced by HIF-EPO and the blood vessel formation induced by VEGF-VEGFR. Here, we established a rat HAPC model and treated it with the HIF-2α inhibitor PT2385. We mainly evaluated the therapeutic effect of PT2385 on HAPC rats by observing the changes in rat phenotype, tissue and organ damage, red blood cell and hemoglobin content, angiogenesis, lipid peroxidation reaction, and inflammatory factors. The results showed that PT2385 treatment improved the congestion phenotype characteristics, inhibited increased erythrocytes and hemoglobin, reduced blood vessel formation, lipid peroxidation, and inflammation, and reduced tissue and organ damage in HAPC rats. This study preliminarly explains the physiological, pathological, and immunological effects of PT2385 treatment for HAPC. It provides a new idea, a reliable experimental basis, and theoretical support for the clinical prevention and treatment of HAPC.

100 Deals associated with PT-2385

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16055

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Recurrent Glioblastoma	Phase 2	US	Peloton Therapeutics, Inc.	14 Sep 2017
Renal Cell Carcinoma	Phase 2	US	Peloton Therapeutics, Inc.	24 Apr 2017
Von Hippel-Lindau Disease	Phase 2	US	Peloton Therapeutics, Inc.	24 Apr 2017
Locally Advanced Clear Cell Renal Cell Carcinoma	Phase 1	US	Peloton Therapeutics, Inc.	25 Nov 2014

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03108066 (MK-3795-003, CTgov)	Phase 2	Von Hippel-Lindau Disease \| Renal Cell Carcinoma	4	MK-3795	wkizzujytk(okahsxggcn) = eluzdkklyb lwzmvpfujm (eoujcxbsfy, zgsnhvmxby - whraktgdvx) View more	-	24 Sep 2024
NCT03216499 (PT2385 \| two-stage single-arm open-label phase II study, CTgov)	Phase 2	Recurrent Glioblastoma	24	Pharmacogenomic Study+HIF-2alpha Inhibitor PT2385	(paiffdixwf) = inywvnfcqs kwljkfzuea (ypauovbcgc, tnnevlofoo - ibkkqmfafy) View more	-	21 Sep 2020
NCT03216499 (ASCO2019) Manual	Phase 2	Glioblastoma	24	PT-2385	vcbguvqugs(imtpiyjabf) = No objective radiographic responses were observed ewtphfyoeq (zdrxeznvod ) View more	Positive	02 Jun 2019
NCT03216499 (ASCO2019) Manual	Phase 2	Glioblastoma	24	PT-2385 (Cmin< 300 on Day 15)		Positive	02 Jun 2019
NCT02293980 (3795-001 \| MK-3795-001, ASCO_GU2019) Manual	Phase 1	Renal Cell Carcinoma	50	PT2385+nivolumab	(oudpowficg) = xwladjldzg vscqlifxyy (broopdiblk ) View more	Positive	16 Feb 2019
NCT02293980 (3795-001 \| MK-3795-001, Pubmed \| J Urol) Manual	Phase 1	Locally Advanced Clear Cell Renal Cell Carcinoma Second line	51	PT2385	(kakbcnjscx) = vfzzopoagt gcjrjaulua (iwtlwxclwf ) View more	Positive	20 Mar 2018
NCT02293980 (3795-001 \| MK-3795-001, ASCO2016)	Phase 1	Locally Advanced Clear Cell Renal Cell Carcinoma	43	PT2385	(ypabnobxqx) = 14 mlszovupik (rlayjzzare ) View more	Positive	20 May 2016