FLT3 inhibitors for the treatment of neuropathic pain – NEUROPATH
NEUROPATH
Neuropathic pain (NP) is a chronic pain disorder caused by nerve damage secondary to other pathologies (eg diabetes), or surgical or traumatic lesions. Treatments for NP are non-specific, inefficient and generate side effects. NEUROPATH researchers found that NP was selectively initiated and maintained by stimulation of the Tyrosine Kinase Receptor FLT3, which therefore appears to be a relevant therapeutic target for NP.
Developing an Effective and Safe Drug for the Treatment of NP
The challenge is to design and develop an effective and well-tolerated molecule for the treatment of NP. As it is a chronic disease, which requires long-term treatments, the issue of drug safety is essential. «Classic« Tyrosine Kinase Receptor (RTK) inhibitors target intracellular kinase, the structure of which is widely conserved among RTKs and other kinases. As a result, they lack specificity and their interaction with other kinases generates side effects, which may be acceptable in the treatment of cancer which also use this type of molecules, but unacceptable for NP. The path chosen by NEUROPATH is innovative but more difficult, since the molecules which are the object of the program target the extracellular part of FLT3, which is unique among RTKs. Thus, the molecules chosen block the interaction between the FLT3 receptor and its FL ligand. They do so in a selective and non-competitive manner; they act as negative allosteric modulators (NAM). A prototype of FLT3 NAM had already been identified, BDT001 (see Rivat et al /, Nat Commun, 2018, 9: 1042), which shows exceptional efficiency in various animal models of NP, by the extent and duration of action of its effect.<br />The objective is now to identify a molecule improved and to develop it until the stage of preclinical candidate ready to enter regulatory development.
The molecules which are the basis of the selection and optimization program come from a high throughput screening The validated and pre-selected hits were subjected to predictive tests of their qualities as future drugs to select the most suitable for development. The chemical series resulting from these hits are then subjected to chemical modulations, then to the same predictive tests, supplemented by pharmacological tests evaluating their effectiveness in NP models. This iterative process is repeated until the selection of a preclinical candidate ready to enter regulatory development.
Potential chemical series emerged from the pre-selection and analogues of the hits were designed and synthesized, then evaluated. One of these series is being improved (elimination of chemical alerts) and a seconde series is also being worked on. Currently, these 2 series are being optimized with the aim of isolating a preclinical candidate. One lead has been identified which exhibits excellent qualities for future development, excellent selectivity to other targets and selectivity for neuronal FLT3. This lead was evaluated in an NP model in rats (the “Chronic Constriction Injury” model).
The other objectives of the program will be achieved in the period covered by ANR funding.
We plan to continue the selection program until obtaining the preclinical candidate. Beyond that, the BIODOL company, coordinator of the project, secured its funding to pursue regulatory development at the end of the ANR program until the authorization of clinical trials was obtained.
1. D. Rognan: FLT3 negative allosteric modulators: from screenings hit to a preclinical candidate, 7th International Conference of Cancer and Ageing, Wuhan (Chine), 28-31 octobre 2019.
2. D. Rognan: FLT3 negative allosteric modulators: from a screening hit to a preclinical candidate, Journée scientifique de la Fédération de Recherche FR2708, Orléans, 25 avril 2019.
3. D. Rognan: FLT3 negative allosteric modulators: from screenings hit to a preclinical candidate, 8th annual meeting of the GDR 3545 GPCR International Meeting, Montpellier, 9-11 octobre 2019.
4. D. Rognan: FL3 negative allosteric modulators: From screening hits to a preclinical candidate. 6th Barrande Meeting, Strasbourg, 23-24 Septembre 2019
Peripheral neuropathic pain (PNP) arises from nerve damage, caused by diabetes herpes zoster infection, cancer therapy, trauma or surgical procedure. PNP is partially resistant to current therapies, which are merely symptomatic and with poor efficacy and safety. PNP stems from aberrant functioning of somatosensory neurons, but the mechanisms have remained largely unraveled. Using various PNP models and means to inhibit FLT3 function, we have identified FLT3 as the upstream target responsible for initiation and maintenance of PNP. By targeting the unique FLT3 extracellular domain, we identified prototypes of extracellular FLT3 inhibitors, which completely reverse PNP. To identify novel compounds with improved features, 48,000 compounds were screened and 10 chemical series were validated. The aims of the NEUROPATH project are to optimize the pharmacodynamic, pharmacokinetic and safety properties of 2 selected chemical series and to identify a Preclinical Candidate, which will be proposed for out-licensing to a pharmaceutical partner. For this program, The Consortium will involve an SME as Coordinator, and 2 academic groups specialized in medicinal chemistry and pain, respectively.
Project coordination
Pierre SOKOLOFF (BIODOL THERAPEUTICS)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
BDT BIODOL THERAPEUTICS
INM Institut des Neurosciences de Montpellier - Déficits Sensoriels et Moteurs
LIT Laboratoire d'Innovation Thérapeutique
Help of the ANR 676,908 euros
Beginning and duration of the scientific project:
March 2019
- 36 Months
