CKAP2 modulators(cytoskeleton associated protein 2 modulators), GNA11 inhibitors(G protein subunit alpha 11 inhibitors), GNAQ inhibitors(G protein subunit alpha q inhibitors)

+ [1]

Therapeutic Areas

NeoplasmsCardiovascular DiseasesDigestive System Disorders+ [3]

Active Indication

Stomach CancerUveal MelanomaVasomotor symptom

Inactive Indication-

Originator Organization

Hoshi University

Active Organization

Hefei Institutes of Physical Science

University of Science & Technology of ChinaThe Holden Comprehensive Cancer Center

+ [1]

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with FR900359

100 Translational Medicine associated with FR900359

100 Patents (Medical) associated with FR900359

Literatures (Medical) associated with FR900359

30 Apr 2025·The FASEB Journal

Gαq/11 Signaling Modulates Fibroblast Growth Factor 23 Production and Contributes to Acute Kidney Injury

Article

Author: Bai, Yi ; He, Qing ; Zhang, Yue ; Zuo, Yiyi ; Jiang, Jie

ABSTRACTFibroblast growth factor 23 (FGF23), primarily secreted by osteocytes and osteoblasts, is essential in regulating phosphate‐calcium metabolism by inhibiting renal phosphate reabsorption and vitamin D synthesis. Acute kidney injury (AKI) is characterized by a rapid deterioration in renal function, accompanied by a significant increase in FGF23 levels, which contribute to its severity and progression. This study investigated the mechanistic roles of Gαq and Gα11 proteins, integral components of the lysophosphatidic acid (LPA) signaling pathway, in the regulation of FGF23 expression during AKI. Through targeted knockdown and pharmacological inhibition of Gαq and Gα11 in the osteoblastic MC3T3‐E1 and osteocytic MLO‐Y4 cells, we demonstrated that individual suppression of these G proteins had minimal impact on both basal and LPA‐stimulated FGF23 levels. In contrast, concurrent knockdown significantly diminished FGF23 expression, implicating a synergistic role of Gαq and Gα11 in FGF23 regulation. This hypothesis was supported by using Gαq/11‐specific inhibitors, YM‐254890 and FR900359, which attenuated LPA‐induced FGF23 upregulation. Our findings further elucidated the downstream signaling events, highlighting the involvement of PKC phosphorylation, intracellular calcium mobilization, and the MAPK/ERK1/2 pathway in mediating FGF23 expression. Moreover, in a folic acid‐induced AKI mouse model, elevated FGF23 levels in bone, bone marrow, and serum were significantly reduced following YM‐254890 administration, underscoring the potential of targeting Gαq/11 signaling in managing AKI‐associated FGF23 dysregulation. This study not only advances our understanding of FGF23 regulation in renal injuries but also identifies Gαq/11 signaling modulation as a promising strategy to alleviate AKI severity and other disorders associated with dysregulated FGF23 levels.

01 Feb 2025·Journal of Pharmacokinetics and Pharmacodynamics

QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life

Article

Author: Wuersch, Kuno ; Khera, Eshita ; Davis, John ; Vostiarova, Helena ; Kearns, Jeffrey D ; Hainzl, Dominik ; Romanet, Vincent ; Sharaby, Sherif ; Engelhardt, Volker ; Ebel, Nicolas ; Dharmarajan, Lekshmi

Antibody drug conjugates (ADC) are a promising class of oncology therapeutics consisting of an antibody conjugated to a payload via a linker. DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. To assess the impact of FR inactivation on DYP688 pharmacology and clinical developability, we performed translational modeling of preclinical PK and tumor growth inhibition (TGI) data, accompanied by mechanistic Krogh cylinder tumor modeling. Using a PK-TGI model, we identified a composite exposure-above-tumorostatic concentration (AUC_TSC) metric as the PK-driver of efficacy. To underpin the mechanisms behind AUC_TSC as the driver of efficacy, we performed quantitative systems pharmacology (QSP) modeling of DYP688 intratumoral pharmacokinetics and pharmacodynamics. Through exploratory simulations, we show that by deviating from canonical ADC design dogma, DYP688 has optimal FR900359 activity despite its transient inactivation. Finally, we performed the successful preclinical to clinical translation of DYP688 PK, including the payload inactivation kinetics, evidenced by good agreement of the predicted PK to the observed interim clinical PK. Overall, this work highlights early quantitative pharmacokinetics as a missing link in the ADC design-developability chasm.

04 Nov 2024·ChemBioChem

Condensation Domain Editing of the FR900359 Assembly Line Yields a Novel Analog Amenable to Late‐Stage Functionalization

Article

Author: Pistorius, Dominik ; Buntin, Kathrin ; Weber, Eric ; Dresen, Kathrin ; Richard, Etienne ; Petersen, Frank ; Wollbrett, Séverine ; Manchado, Eusebio ; Haberkorn, Anne

AbstractThe natural product FR900359 (FR) has generated significant attention lately, due to its characteristics as potent and selective inhibitor of Gq/11 mediated signal transduction of associated G protein‐coupled receptors (GPCRs). This makes FR both a widely used pharmacological tool compound and a lead molecule for targeted cancer therapy. The exploration of structure‐activity‐relationship (SAR) of the scaffold by total synthesis has been complicated by its structural complexity and its incompatibility with standard approaches of solid‐phase peptide synthesis. Options for late‐stage functionalization of FR are limited due to a lack of tractable functional groups. Here we present a mixed approach combining (i) genetic engineering of the FR‐assembly line in Chromobacterium vaccinii, to obtain a novel FR analog featuring a primary amine, with (ii) its subsequent synthetic modification and biological profiling for further SAR exploration of the FR scaffold.

100 Deals associated with FR900359

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Stomach Cancer	Preclinical	China	Hefei Institutes of Physical Science	12 Feb 2025
Stomach Cancer	Preclinical	China	University of Science & Technology of China	12 Feb 2025
Uveal Melanoma	Preclinical	United States	The Holden Comprehensive Cancer Center	22 Mar 2024
Vasomotor symptom	Preclinical	Japan	Hoshi University	03 Mar 2012

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