Pimicotinib is a CSF1R inhibitor (antagonist) with anti-tumor activity.

Physicochemical Properties

Molecular Formula	C22H24N6O3
Molecular Weight	420.464364051819
Exact Mass	420.19
Elemental Analysis	C, 62.84; H, 5.75; N, 19.99; O, 11.42
CAS #	2253123-16-7
Related CAS #	2866305-19-1 (HCl); 2253123-16-7
PubChem CID	139549388
Appearance	White to off-white solid powder
LogP	2
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	4
Heavy Atom Count	31
Complexity	674
Defined Atom Stereocenter Count	0
InChi Key	NXFPMDWYDKHFMM-UHFFFAOYSA-N
InChi Code	InChI=1S/C22H24N6O3/c1-14-18(31-16-7-9-23-17(11-16)15-12-24-27(4)13-15)5-6-19(25-14)26-21(30)28-10-8-22(2,3)20(28)29/h5-7,9,11-13H,8,10H2,1-4H3,(H,25,26,30)
Chemical Name	3,3-dimethyl-N-[6-methyl-5-[2-(1-methylpyrazol-4-yl)pyridin-4-yl]oxypyridin-2-yl]-2-oxopyrrolidine-1-carboxamide
Synonyms	pimicotinib [INN]; Pimicotinib (USAN/INN); HV1XI8HST2; ABSK021; ABSK-021; CHEMBL5314535;
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	CSF1R/colony stimulating factor 1 receptor
ln Vitro	An N-(azaaryl)cyclolactam-1-carboxamide derivative having a structure of formula (1), a preparation method therefor, and a use thereof, each substituent being defined in the description and claims. The compound can be widely applied to the preparation of medicaments for treating cancer, tumor, autoimmune diseases, metabolic diseases, or metastatic diseases, in particular for treating ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, or bone metastatic cancer, and is expected to be developed into CSF1R inhibitor drugs[1].
ln Vivo	Tenosynovial giant cell tumor (TGCT) is a rare, locally invasive soft tissue tumor arising from the synovium of joints, bursa and tendon sheaths and is associated with the overexpression of the colony-stimulating factor 1 (CSF-1) gene. Pimicotinib is an orally available, highly selective and potent small molecule CSF-1 receptor (CSF-1R) inhibitor with robust efficacy and safety profile in patients with TGCT and is under development in multiple diseases. In an open-label Phase I study in patients with TGCT not amenable to surgery, pimicotinib showed superior efficacy and safety. In this article, we elucidate the rationale and study design of the multi-region Phase III MANEUVER trial (NCT05804045), which is designed to assess the efficacy and safety of pimicotinib in patients with TGCT not amenable to surgical resection in Asia, North America and Europe [2].
Animal Protocol	Randomization & Blinding [2] Approximately 90 eligible participants will be randomized in a 2:1 ratio to pimicotinib 50 mg QD or matching placebo (Figure 1). Randomization will be conducted across all sites using a central interactive web response system and will be stratified by China sites and non-China sites. In Part 1, treatment assignment will remain blinded to participants, investigators, study site personnel, safety laboratory personnel, central imaging readers and reviewers, as well as the sponsor. After all participants complete Part 1 and reach the primary efficacy analysis time point, unblinding (for the sponsor only) and analysis will be conducted following data cleaning and database lock. Study interventions [2] Pimicotinib or matching placebo is administered QD with a dose of 50 mg in Part 1, and the drug can be taken with or without food. Participants will continue with the same dosage in Part 2 (and Part 3, if applicable) as they were receiving at the conclusion of Part 1. The study drug may be interrupted or dose reduced at the investigator's discretion at any time, e.g., due to AEs. A reduction to 25 mg QD is permissible as the maximum dose adjustment. If a participant requires a therapeutic dose below 25 mg QD, they must discontinue from the treatment. Safety & AEs [2] An AE is defined as any untoward medical occurrence, regardless of its causal relationship to the investigational drug, that occurs in a participant from the time of signing the informed consent form until 30 days (including Day 30) after the last dose of study drug. A treatment-emergent adverse event (TEAE) is defined as any adverse event that occurs or worsens after the initiation of treatment in this study, up to 30 days after the last dose of the study drug, following guidance from the US FDA. The severity of AEs will be graded by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
References	[1]. N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method and application. World Intellectual Property Organization, WO2018214867 A1. 2018-11-29. [2]. MANEUVER: A Phase III study of pimicotinib to assess efficacy and safety in tenosynovial giant cell tumor patients. Future Oncol . 2024 Sep 17:1-8.
Additional Infomation	Pimicotinib is an orally bioavailable inhibitor of colony stimulating factor 1 receptor (CSF1R; CSF-1R; CD115; M-CSFR), with potential immunomodulatory and antineoplastic activities. Upon oral administration, pimicotinib targets and binds to CSF1R, thereby blocking CSF1R activation and CSF1R-mediated signaling. This inhibits the activities of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), and prevents immune suppression in the tumor microenvironment (TME). This enhances antitumor T-cell immune responses and inhibits the proliferation of tumor cells. CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) and CD115 (cluster of differentiation 115), is a cell-surface receptor that plays major roles in tumor cell proliferation and metastasis. Tenosynovial giant cell tumor (TGCT) is a rare soft tissue tumor which grows in the soft tissues around joints or parts of the body used for movement. It is caused by high levels of a type of protein called CSF-1. Even though surgery is a preferred treatment option, some patients may be unable to have surgery because of where the tumor is, how complicated it is, or the risk of serious problems or illness after the surgery. Therefore, new treatments that are safe, effective and that help people live well are still needed for this disease. Pimicotinib is a medicine which blocks CSF-1, and researches have shown that it is safe and effective for treating TGCT in smaller, early study. To confirm these results, researchers have started a larger study, known as MANEUVER, in some parts of Asia, North America and Europe. This study will confirm if pimicotinib is safe and effective in patients with TGCT who may not be able to have surgery.Clinical Trial Registration: NCT05804045 (ClinicalTrials.gov).[2] The MANEUVER study is structured around a robust three-part design, initiating with a blinded assessment of efficacy and safety, followed by an extended open-label phase that allows for longer observation of secondary end points. Notably, the trial incorporates a placebo crossover component, which is anticipated to strengthen the evidence supporting the efficacy and safety of pimicotinib beyond part 1. Besides objective imaging assessment, most key secondary analyses will focus on several clinical outcome assessments. These measures are critical for demonstrating that pimicotinib offers significant clinical benefits. Furthermore, it is imperative to confirm the absence of conventional hepatotoxicity associated with pimicotinib based on the data from Phase I study. The study's outcomes are expected to clarify pimicotinib's role as a therapeutic option for patients requiring interventions to preserve physical function and enhance quality of life. Most importantly, these results will provide a deeper understanding of disease characteristics and potential variations in response across different populations, i.e. the Chinese and western population. This is the first global trial to enroll both Asian and Western patients with TGCT in balanced proportions across multiple regions. Specifically, Asian participants, primarily from China, constitute half of our study population. This robust representation allows for detailed outcome comparisons by stratification factor – China sites versus non-China sites – thereby facilitating a deeper understanding of disease characteristics and potential variations in response across different populations. While previous research has documented similar anatomical distributions between Chinese and Western patient populations with TGCT, notable disparities in the mean duration from disease onset to diagnosis and histories of previous trauma have been observed [Citation15,Citation16]. This will address critical gaps in existing literature and advance our comprehension of the clinical landscape of TGCT in varied demographic settings.[2]

Solubility Data

Solubility (In Vitro)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.3783 mL	11.8917 mL	23.7835 mL
	5 mM	0.4757 mL	2.3783 mL	4.7567 mL
	10 mM	0.2378 mL	1.1892 mL	2.3783 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.