Last update 01 Nov 2024

CaN x FKBP12

Last update 01 Nov 2024

Basic Info

Related Targets

CaNFKBP12

Drugs associated with CaN x FKBP12

LP-410

Target

CaN x FKBP12

Mechanism

CaN inhibitors [+1]

Active Org.

Lipella Pharmaceuticals, Inc.

Originator Org.

Lipella Pharmaceuticals, Inc.

Active Indication

Graft vs Host Disease

Inactive Indication-

Drug Highest PhaseIND Approval

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CaN x FKBP12

100 Translational Medicine associated with CaN x FKBP12

0 Patents (Medical) associated with CaN x FKBP12

204

Literatures (Medical) associated with CaN x FKBP12

11 Jan 2024·Chemistry – A European Journal

Generation of Bioactivity‐Tailored FK506/FK520 Analogs by CRISPR Editing in Streptomyces tsukubaensis

Article

Author: Drčar, Tjasa ; Buntin, Kathrin ; Pivk Lukančič, Petra ; Salcius, Michael ; Mrak, Peter ; Regenass, Hugo ; Weber, Eric ; Wollbrett, Séverine ; Koplan, Eva ; Thibaut, Christian ; Gao, Xiaolin ; Krastel, Philipp ; Wang, Shaowen

AbstractFor a potential application of FK506 in the treatment of acute kidney failure only the FKBP12 binding capability of the compound is required, while the immunosuppressive activity via calcineurin binding is considered as a likely risk to the patients. The methoxy groups at C13 and C15 are thought to have significant influence on the immunosuppressive activity of the molecule. Consequently, FK506 analogs with different functionalities at C13 and C15 were generated by targeted CRISPR editing of the AT domains in module 7 and 8 of the biosynthetic assembly line in Streptomyces tsukubaensis. In addition, the corresponding FK520 (C21 ethyl derivative of FK506) analogs could be obtained by media adjustments. The compounds were tested for their bioactivity in regards to FKBP12 binding, BMP potentiation and calcineurin sparing. 15‐desmethoxy FK506 was superior to the other tested analogs as it did not inhibit calcineurin but retained high potency towards FKBP12 binding and BMP potentiation.

10 Nov 2023·ACS Pharmacology & Translational Science

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

Review

Author: Schade, Dennis ; Riege, Daniel ; Fenkl, Teresa ; Herschel, Sven

The bone morphogenetic protein (BMP) pathway is highly conserved and plays central roles in health and disease. The quality and quantity of its signaling outputs are regulated at multiple levels, offering pharmacological options for targeted modulation. Both target-centric and phenotypic drug discovery (PDD) approaches were applied to identify small-molecule BMP inhibitors and stimulators. In this Review, we accumulated and systematically classified the different reported chemotypes based on their targets as well as modes-of-action, and herein we illustrate the discovery history of selected candidates. A comprehensive summary of available biochemical, cellular, and in vivo activities is provided for the most relevant BMP modulators, along with recommendations on their preferred use as chemical probes to study BMP-related (patho)physiological processes. There are a number of high-quality probes used as BMP inhibitors that potently and selectively interrogate the kinase activities of distinct type I (16 chemotypes available) and type II receptors (3 chemotypes available). In contrast, only a few high-quality BMP stimulator modalities have been introduced to the field due to a lack of profound target knowledge. FK506-derived macrolides such as calcineurin-sparing FKBP12 inhibitors currently represent the best-characterized chemical tools for direct activation of BMP-SMAD signaling at the receptor level. However, several PDD campaigns succeeded in expanding the druggable space of BMP stimulators. Albeit the majority of them do not entirely fulfill the strict chemical probe criteria, many chemotypes exhibit unique and unrecognized mechanisms as pathway potentiators or synergizers, serving as valuable pharmacological tools for BMP perturbation.

31 Oct 2023·mBio

Enhanced fungal specificity and in vivo therapeutic efficacy of a C-22-modified FK520 analog against C. neoformans

Article

Author: Heitman, Joseph ; Rivera, Angela ; Pina-Oviedo, Sergio ; Park, Eunchong ; Dome, Patrick A. ; Steinbach, William J. ; Hong, Jiyong ; Sun, Sheng ; Young Lim, Won ; Spasojevic, Ivan ; Ciofani, Maria ; Averette, Anna Floyd ; Hoy, Michael J. ; Juvvadi, Praveen R.

ABSTRACT Fungal infections are of mounting global concern, and the current limited treatment arsenal poses challenges when treating such infections. In particular, infections by Cryptococcus neoformans are associated with high mortality, emphasizing the need for novel therapeutic options. Calcineurin is a protein phosphatase that mediates fungal stress responses, and calcineurin inhibition by the natural product FK506 blocks C. neoformans growth at 37°C. Calcineurin is also required for pathogenesis. However, because calcineurin is conserved in humans and inhibition with FK506 results in immunosuppression, the use of FK506 as an anti-infective agent is precluded. We previously elucidated the structures of multiple fungal calcineurin-FK506-FKBP12 complexes and implicated the C-22 position on FK506 as a key point for differential modification of ligand inhibition of mammalian versus fungal target proteins. Through in vitro antifungal and immunosuppressive testing of FK520 (a natural analog of FK506) derivatives, we identified JH-FK-08 as a lead candidate for further antifungal development. JH-FK-08 exhibited significantly reduced immunosuppressive activity and both reduced fungal burden and prolonged survival of infected animals. JH-FK-08 exhibited additive activity in combination with fluconazole in vivo . These findings further advance calcineurin inhibition as an antifungal therapeutic approach. IMPORTANCEFungal infections cause significant morbidity and mortality globally. The therapeutic armamentarium against these infections is limited, and the development of antifungal drugs has been hindered by the evolutionary conservation between fungi and the human host. With rising resistance to the current antifungal arsenal and an increasing at-risk population, there is an urgent need for the development of new antifungal compounds. The FK520 analogs described in this study display potent antifungal activity as a novel class of antifungals centered on modifying an existing orally active FDA-approved therapy. This research advances the development of much-needed newer antifungal treatment options with novel mechanisms of action.

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