Delving into the Latest Updates on PF-04929113 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [2]

Target

HSP90

Mechanism

HSP90 inhibitors(Heat shock 90kDa proteins inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

Adenocarcinoma of LungChronic Lymphocytic LeukemiaHematologic Neoplasms+ [6]

Originator Organization

Serenex, Inc.

Active Organization-

Inactive Organization

Esanex, Inc.

Pfizer Inc.

Serenex, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC25H30F3N5O4

InChIKeyAVDSOVJPJZVBTC-CTYIDZIISA-N

CAS Registry908115-27-5

SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical response in subjects who have residual disease, but have not progressed on ibrutinib after 18 months of monotherapy, and/or prevents or delays disease progression of subjects with CLL.

Start Date07 Feb 2017

Sponsor / Collaborator

Esanex, Inc.

NCT02914327 / WithdrawnPhase 1

A Phase 1, Open-label Study of SNX-5422 and Ibrutinib in Chronic Lymphocytic Leukemia Subjects With a Mutation in Bruton's Tyrosine Kinase

SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will result in the removal of mutated BTK from blood mononuclear cells and/or prevents or delays disease progression of subjects with CLL

Start Date02 Feb 2017

Sponsor / Collaborator

Esanex, Inc.

NCT02612285 / TerminatedPhase 2

A Single Arm Study of SNX-5422 in Subjects With TP53 Null Cancers

SNX-5422 is a pro-drug of SNX-2112, a potent, highly selective, small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). Initial in vitro evidence supports that SNX-5422 may be active against TP53 null tumors irrespective of tumor type .

Start Date01 Mar 2016

Sponsor / Collaborator

Esanex, Inc.

100 Clinical Results associated with PF-04929113

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100 Translational Medicine associated with PF-04929113

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100 Patents (Medical) associated with PF-04929113

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29

Literatures (Medical) associated with PF-04929113

01 Feb 2024·Journal of Pharmacology and Experimental Therapeutics

HSP90, a Common Therapeutic Target for Suppressing Skin Injury Caused by Exposure to Chemically Diverse Classes of Blistering Agents

Article

Author: Srivastava, Ritesh Kumar ; Muzaffar, Suhail ; Crossman, David K ; Khan, Jasim ; Athar, Mohammad ; Agarwal, Anupam

Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates, namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES), respectively, we defined a common underlying mechanism of toxic action by these two distinct classes of vesicants. Murine skin exposure to these chemicals causes tissue destruction characterized by increase in skin bifold thickness, Draize score, infiltration of inflammatory cells, and apoptosis of epidermal and dermal cells. RNA sequencing analysis identified ∼346 inflammatory genes that were commonly altered by both PAO and CEES, along with the identification of cytokine signaling activation as the top canonical pathway. Activation of several proinflammatory genes and pathways is associated with phosphorylation-dependent activation of heat shock protein 90α (p-HSP90α). Topical treatment with known HSP90 inhibitors SNX-5422 and IPI-504 post PAO or CEES skin challenge significantly attenuated skin damage including reduction in overall skin injury and clinical scores. In addition, highly upregulated inflammatory genes Saa3, Cxcl1, Ccl7, IL-6, Nlrp3, Csf3, Chil3, etc. by both PAO and CEES were significantly diminished by treatment with HSP90 inhibitors. These drugs not only reduced PAO- or CEES-induced p-HSP90α expression but also its client proteins NLRP3 and pP38 and the expression of their target inflammatory genes. Our data confirm a critical role of HSP90 as a shared underlying molecular target of toxicity by these two distinct vesicants and provide an effective and novel medical countermeasure to suppress vesicant-induced skin injury. SIGNIFICANCE STATEMENT: Development of effective and novel mechanism-based antidotes that can simultaneously block cutaneous toxic manifestations of distinct vesicants is important and urgently needed. Due to difficulties in determining the exact nature of onsite chemical exposure, a potent drug that can suppress widespread cutaneous damage may find great utility. Thus, this study identified HSP90 as a common molecular regulator of cutaneous inflammation and injury by two distinct warfare vesicants, arsenicals and mustards, and HSP90 inhibitors afford significant protection against skin damage.

01 Nov 2023·Biochemical Pharmacology

High-throughput screening as a drug repurposing strategy for poor outcome subgroups of pediatric B-cell precursor Acute Lymphoblastic Leukemia

Article

Author: Valsecchi, Maria Grazia ; Bardini, Michela ; Savino, Angela Maria ; Valsecchi, Luigia ; Scharov, Katerina ; Palmi, Chiara ; Borkhardt, Arndt ; Silvestri, Daniela ; Watrin, Titus ; Vogt, Melina ; Fazio, Grazia ; Tu, Jia-Wey ; Quadri, Manuel ; Biondi, Andrea ; Bhatia, Sanil ; Procopio, Simona ; Cazzaniga, Giovanni ; Oikonomou, Athanasios

Although a great cure rate has been achieved for pediatric BCP-ALL, approximately 15% of patients do not respond to conventional chemotherapy and experience disease relapse. A major effort to improve the cure rates by treatment intensification would result in an undesirable increase in treatment-related toxicity and mortality, raising the need to identify novel therapeutic approaches. High-throughput (HTP) drug screening enables the profiling of patients' responses in vitro and allows the repurposing of compounds currently used for other diseases, which can be immediately available for clinical application. The aim of this study was to apply HTP drug screening to identify potentially effective compounds for the treatment of pediatric BCP-ALL patients with poor prognosis, such as patients with Down Syndrome (DS) or carrying rearrangements involving PAX5 or KMT2A/MLL genes. Patient-derived Xenografts (PDX) samples from 34 BCP-ALL patients (9 DS CRLF2r, 15 PAX5r, 10 MLLr), 7 human BCP-ALL cell lines and 14 hematopoietic healthy donor samples were screened on a semi-automated HTP drug screening platform using a 174 compound library (FDA/EMA-approved or in preclinical studies). We identified 9 compounds active against BCP-ALL (ABT-199/venetoclax, AUY922/luminespib, dexamethasone, EC144, JQ1, NVP-HSP990, paclitaxel, PF-04929113 and vincristine), but sparing normal cells. Ex vivo validations confirmed that the BCL2 inhibitor venetoclax exerts an anti-leukemic effect against all three ALL subgroups at nanomolar concentrations. Overall, this study points out the benefit of HTP screening application for drug repurposing to allow the identification of effective and clinically translatable therapeutic agents for difficult-to-treat childhood BCP-ALL subgroups.

01 Dec 2021·Lung Cancer

Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers

Article

Author: Giuseppe Giaccone ; Zhonglin Hao ; Alexander Drilon ; Everardus Otto Orlemans ; Robin Guo ; Mark G. Kris ; Martin Gutierrez ; James M. Hinson ; Christie Hilton ; Stephen V. Liu

OBJECTIVESSingle-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers.MATERIALS AND METHODSIn part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m²) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m²) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m² SNX-5422 monotherapy qod for 21 days (28-day cycle).RESULTSTwenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m² qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion).CONCLUSIONSThe triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.

100 Deals associated with PF-04929113

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06070

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Lymphocytic Leukemia	Phase 2	US	Esanex, Inc.	02 Feb 2017
Neoplasms	Phase 2	US	Esanex, Inc.	01 Mar 2016
Neuroendocrine Tumors	Phase 2	US	Esanex, Inc.	01 Feb 2014
HER2 Positive Cancer	Phase 2	US	Esanex, Inc.	01 Apr 2013
Adenocarcinoma of Lung	Phase 2	US	Esanex, Inc.	01 Mar 2013
Hematologic Neoplasms	Phase 2	US	Serenex, Inc.	01 Jan 2008
Non-Hodgkin Lymphoma	Phase 2	US	Pfizer Inc.	01 Jun 2007
Non-Hodgkin Lymphoma	Phase 2	US	Esanex, Inc.	01 Jun 2007
Refractory Malignant Solid Neoplasm	Phase 2	US	Esanex, Inc.	01 Jun 2007
Refractory Malignant Solid Neoplasm	Phase 2	US	Pfizer Inc.	01 Jun 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02612285 (CTgov)	Phase 2	Neoplasms	1	SNX-5422	pejatpfubm(ozgkwrftew) = srwpiyscly rkuymdqtgs (dlyckwgwyg, gfgzrvmwsk - regqvbfsvy) View more	-	14 Nov 2018
NCT01892046 (ASCO2017) Manual	Phase 1	Advanced Lung Non-Small Cell Carcinoma	20	carboplatin+paclitaxel+SNX-5422	(bhlmqldpzq) = 4 pts：diarrhea (1 pt discontinued), increased alanine aminotransferase/aspartate aminotransferase (ALT/AST) (1), nausea, vomiting, and diarrhea (1), and peripheral sensory neuropathy (1). jwaxwlflte (pjxewngorb ) View more	Positive	02 Jun 2017
NCT01848756 (CTgov)	Phase 1/2	HER2 Positive Cancer	15	SNX-5422	cztlxspgud(gohobempyr) = fttlxwnqoj epoqhfvzpm (rcbvwpdsoh, lfjjoxrakq - usztpjdtnv) View more	-	21 Nov 2016