Delving into the Latest Updates on PT-2385 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

PT 2385, PT2385

Target

HIF-2α

Action

inhibitors

Mechanism

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

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Metastatic Clear Cell Renal Cell CarcinomaLocally Advanced Clear Cell Renal Cell Carcinoma

Inactive Indication

Recurrent GlioblastomaVon Hippel-Lindau Disease

Originator Organization

Peloton Therapeutics, Inc.

Active Organization

Peloton Therapeutics, Inc.

The University of Texas Southwestern Medical Center

Inactive Organization-

License Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure/Sequence

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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64

Literatures (Medical) associated with PT-2385

31 Dec 2025·RENAL FAILURE

Hypoxia-inducible factor 2α overexpression in podocytes ameliorates lipid metabolism disorders in diabetic kidney disease by inhibiting S1P

Article

Author: Wang, Mingming ; Wang, Qimeng ; Liu, Gang ; Yang, Xue ; Nie, Huibin ; Li, Shan ; Wang, Yinghui ; Liu, Qingzhen

Background and aims: Lipid accumulation in podocytes is a major driver of diabetic kidney disease (DKD). Hypoxia-inducible factor 2α (HIF-2α) plays an important role in regulating metabolism. The function of HIF-2α in lipid metabolism in podocytes and the progression of DKD remain unclear.Methods: We investigated the effects of HIF-2α on podocyte damage and lipid metabolism using immunofluorescence, flow cytometry, ELISA, and Western blotting. In order to characterize the regulatory effects of HIF-2α, we also used ChIP and dual-luciferase reporter assays to investigate the role of sphingosine kinase 1 (SPHK1), a crucial enzyme in sphingosine-1-phosphate (S1P) synthesis. In vivo, the effect of HIF-2α on lipid metabolism disorders in db/db mice was investigated using the HIF-2α inhibitor PT-2385.Results: Our results revealed that HIF-2α overexpression improved lipid metabolism in DKD by enhancing cholesterol efflux via reduced S1P synthesis in podocytes by 25.69%. Inhibition of HIF-2α expression in the mouse model of diabetes exacerbated podocyte damage and proteinuria. Inhibition of SPHK1 expression rescued HIF-2α knockdown-mediated lipid disorders in podocytes. HIF-2α inhibited the transcription of SPHK1 by binding to the promoter region of SPHK1 and reduced S1P synthesis. Furthermore, we found that FG-4592, a HIF prolyl hydroxylase inhibitor, reduced the total cholesterol level in DKD by activating HIF-2α, thereby protecting against DKD.Conclusion: HIF-2α ameliorated lipid metabolism disorders and podocyte damage in DKD by downregulating S1P, providing a novel insight for HIF-2α against DKD.

01 Nov 2025·ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY

Low Wall Shear Stress Promotes Atheroma via Arterial Iron Accumulation

Article

Author: Yang, Liu ; Cai, Jing ; Zhang, Zhenxi ; Cheng, Chen ; Li, Kuanyu ; Chen, Zhipeng ; Ji, Run ; Qiao, Tong ; Liu, Yutong ; Zhao, Biao ; Zheng, Lei

BACKGROUND::

Low wall shear stress (WSS) at arterial bifurcations and curves damages endothelial cells, promoting the development of atherosclerosis. Although the accumulation of iron in plaques has been observed, the mechanisms behind it and its effects are not fully understood.

METHODS::

Detect the iron content in different parts of the mouse partial carotid artery ligation model and the aorta. The chelating iron therapy was used to assess the impact of low WSS–induced iron accumulation and atherosclerosis in the arterial wall. In vitro experiments utilized human umbilical vein endothelial cells and an orbital-shaker model to simulate WSS. Mice with endothelial cell–specific knockout of IRP2 (iron regulatory protein 2) and deletion of Apoe (Apolipoprotein e; Apoe−/−IRP2iEcko ) were constructed, as well as a human umbilical vein endothelial cell line with IRP2 knockdown.

RESULTS::

We investigated the iron accumulation induced by low WSS in carotid arteries. Hinokitiol, an iron chelator, was found to reduce this iron buildup and decrease the progression of atherosclerosis. Low WSS in the carotid arteries led to chronic iron accumulation, which altered the expression of iron metabolism–related proteins in endothelial cells, particularly IRP2. Knocking down IRP2 in endothelial cells resulted in an increase in the expression of inflammation-related proteins and a significant elevation in the expression of HIFs (hypoxia-inducible factors). Apoe−/−IRP2iEcko mice exhibited an increased susceptibility to atherosclerosis. The use of HIF inhibitors, PX-478 and PT-2385, was able to suppress the exacerbation of atherosclerosis in Apoe−/− mice caused by the endothelial cell–specific knockout of IRP2 .

CONCLUSIONS::

Our results indicate that low WSS–induced endothelial cell iron metabolism abnormalities, by inducing arterial wall iron accumulation and abnormal expression of iron metabolism–related proteins, promote the occurrence and development of atherosclerosis. The use of iron chelators can alleviate the onset and progression of low WSS–induced atherosclerosis.

01 Dec 2025·UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS

Renal surgery following HIF-2α antagonist therapy: Surgical indications, outcomes and growth kinetics

Article

Author: Merino, Maria J ; Nethala, Daniel ; Azar, William ; Rathi, Nityam ; Miller, Matthew ; Vocke, Cathy D ; Koller, Christopher ; Linehan, W Marston ; Ricketts, Christopher J ; Kenigsberg, Alexander P ; Hesswani, Charles ; Hyman, Jason ; Mendhiratta, Neil ; Millan, Braden ; Srinivasan, Ramaprasad ; Lawson, Keith ; Schuppe, Kyle ; Ball, Mark W ; Parikh, Sahil ; Gurram, Sandeep ; Hsueh, Jessica

BACKGROUND:

The development of HIF-2α antagonists marked an advancement in the treatment of localized VHL-deficient kidney cancer; however, their impact on subsequent surgical interventions remains unexplored. This study investigated the indications for and outcomes of patients undergoing renal surgery after exposure to HIF-2α antagonists and the growth rates (GR) of their index renal tumors.

DESIGN, SETTING, AND PARTICIPANTS:

We performed a retrospective analysis of patients who underwent renal surgery at a single institution following or during treatment with a HIF-2α antagonist. Data regarding the clinicopathologic characteristics, therapy management, and surgical outcomes were collected. Index tumor GRs before, during and after drug administration were calculated and compared.

RESULTS AND LIMITATIONS:

Twenty-seven patients underwent 28 surgeries after exposure to a HIF-2α antagonist from 2015 to 2023, with a total of 82 tumors removed. About 24 patients were treated with Belzutifan, and 3 patients were treated with PT2385, with 26 patients having a diagnosis of VHL syndrome. The median time on therapy prior to surgery was 14.7 months, with a median washout time of drug to surgery of 10 days. Median preoperative hemoglobin prior to surgery was 11.6 g/dL. Two blood transfusions were administered, 1 intraoperatively and 1 postoperatively. Seven postoperative complications were noted, 2 of which were ≥ Grade 3. The median index tumor GR prior to treatment was 0.37 cm/y, 0.46 cm/y during treatment, and 0.54 cm/y post-treatment. There was no significant difference in GRs between the groups. Median time to restart HIF-2α antagonist after surgery was 43 days. Limitations of this study include retrospective nature, single center, and lack of control group.

CONCLUSIONS:

Renal surgery after or during exposure to a HIF-2α antagonist is safe and feasible, with rates of both transfusions and complications commensurate with the reported literature from standard renal surgery. GRs of index renal tumors that eventually needed surgical intervention did not show a significant difference before, during, and after therapy. Tumors exhibiting a positive GR on drug may represent the indication that drives early surgical intervention prior to the tumor reaching the 3 cm threshold. A median washout time of 10 days from last dose of HIF-2α antagonist to surgery was safe and well tolerated.

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	United States	Peloton Therapeutics, Inc.	14 Sep 2017
Renal Cell Carcinoma	Phase 2	United States	Peloton Therapeutics, Inc.	24 Apr 2017
Von Hippel-Lindau Disease	Phase 2	United States	Peloton Therapeutics, Inc.	24 Apr 2017
Metastatic Clear Cell Renal Cell Carcinoma	Phase 1	United States	The University of Texas Southwestern Medical Center	18 Aug 2021
Locally Advanced Clear Cell Renal Cell Carcinoma	Phase 1	United States	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	jsgrqpgxzj = mdcwzbbaht gmnjginbyz (gfaugwzluy, jzfrdenpbi - tqxilwbdmx) View more	-	24 Sep 2024
NCT03216499 (two-stage single-arm open-label phase II study, Pubmed \| J Neurooncol)	Phase 2	Recurrent Glioblastoma HIF2-alpha	24	PT2385 800 mg b.i.d.	ueelgoomdh(zfmfbkwcbm) = xbwieevywt xdlujmvfiw (auuptgcrqt, 4.9 - 12.6) View more	Negative	01 Oct 2023
NCT03216499 (PT2385 \| two-stage single-arm open-label phase II study, CTgov)	Phase 2	Recurrent Glioblastoma	24	Pharmacogenomic Study+HIF-2alpha Inhibitor PT2385	vzlqhrxavy(yjkzjjkurf) = qynoxfnlcf zvqbiodmym (qoirnbxoff, vfcvcjelwi - palzndikvm) View more	-	21 Sep 2020
NCT03216499 (ASCO 12019 \| ASCO 22019) Manual	Phase 2	Glioblastoma	24	PT-2385	jpvstbxndb(satpdegazv) = No objective radiographic responses were observed dykxjwylrc (inoewstcmi ) View more	Positive	02 Jun 2019
NCT03216499 (ASCO 12019 \| ASCO 22019) Manual	Phase 2	Glioblastoma	24	PT-2385 (Cmin< 300 on Day 15)		Positive	02 Jun 2019
NCT02293980 (3795-001 \| MK-3795-001, ASCO_GU 12019 \| ASCO_GU 22019) Manual	Phase 1	Renal Cell Carcinoma	50	PT2385+nivolumab	lakqjznbdt(twkefyddcy) = kmbncjwufm dberudmnqz (aogmixvjyo ) View more	Positive	16 Feb 2019
SNO2018	Phase 2	Recurrent Glioblastoma MGMT promoter	24	PT2385 800 mg b.i.d.	ubudmeerpn(mpbnxlkear) = eztudgjwet dyibcjueko (mxlfyjweje, 4.66 - 12.3)	Negative	05 Nov 2018
NCT02293980 (3795-001 \| MK-3795-001, Pubmed \| J Urol \| J Clin Oncol) Manual	Phase 1	Locally Advanced Clear Cell Renal Cell Carcinoma Second line	51	PT2385	mmgqiaqpqm(mrstnteubs) = wwdqggbgek qctxbvptsr (fefearlyyp ) View more	Positive	20 Mar 2018
NCT02293980 (3795-001 \| MK-3795-001, ASCO2016)	Phase 1	Locally Advanced Clear Cell Renal Cell Carcinoma	43	PT2385	exjjquzgvu(qxwffbvxpz) = 14 ysmdqgpmlf (pephylfmoo ) View more	Positive	20 May 2016