Momelotinib (formerly CYT-387; CYT-11387; LM-1149; Ojjaara), an aminopyrimidine analog, is a novel, potent and ATP-competitive inhibitor of Janus kinases (JAK1/2) with potential antitumor and anti-inflammatory activity. It inhibits JAK1/2 with IC50s of 11 nM/18 nM, and shows ~10-fold selectivity for JAK1/2 over JAK3. CYT 387 is currently undergoing Phase I/II clinical trials for treating myelofibrosis. Momelotinib shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. It was discovered by high-throughput enzyme and cell-based screening along with the optimization using structure-guided medicinal chemistry. Momelotinib (Ojjaara) was approved in 2023 by FDA for treating Myelofibrosis in adults with anaemia.

Physicochemical Properties

Molecular Formula	C23H22N6O2
Molecular Weight	414.46
Exact Mass	414.18
CAS #	1056634-68-4
Related CAS #	Momelotinib sulfate;1056636-06-6;Momelotinib Mesylate;1056636-07-7
PubChem CID	25062766
Appearance	Light yellow to yellow solid powder
Density	1.3±0.1 g/cm3
Index of Refraction	1.646
LogP	1.22
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	6
Heavy Atom Count	31
Complexity	615
Defined Atom Stereocenter Count	0
InChi Key	ZVHNDZWQTBEVRY-UHFFFAOYSA-N
InChi Code	InChI=1S/C23H22N6O2/c24-10-12-25-22(30)18-3-1-17(2-4-18)21-9-11-26-23(28-21)27-19-5-7-20(8-6-19)29-13-15-31-16-14-29/h1-9,11H,12-16H2,(H,25,30)(H,26,27,28)
Chemical Name	N-(cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide.
Synonyms	LM-1149 , CYT-11387; LM 1149 , CYT 11387; LM1149 , CYT11387; CYT-387; Momelotinib; Momelotinib free base; CYT387; CYT 387; Ojjaara
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

ln Vitro	Momelotinib (CYT387) has an IC50 of 1400 nM, which suppresses the proliferation of parental Ba/F3 cells (Ba/F3-wt) triggered by IL-3. Furthermore, Momelotinib (CYT387), with an IC50 of 200, reduces the proliferation of cell lines activated by JAK2 or MPL signaling, such as Ba/F3-MPLW515L cells, CHRF-288-11 cells, and Ba/F3-TEL-JAK2 cells. 700 nM, 1 nM, and nM. Furthermore, it has been demonstrated that momelotinib (CYT387), with an IC50 of 2 μM–4 μM, also potently inhibits the formation of erythrocyte colonies in individuals with JAK2V617F-positive PV in vitro [1]. IGF-1 and IL-6-induced Ras/MAPK and PI3K/AKT activation are inhibited by momelotinib (CYT387). Additionally, in primary multiple myeloma (MM) cells, momelotinib (CYT387) promotes apoptosis as a single agent and synergizes with conventional anti-MM medications PS-341 and L-PAM [2].
ln Vivo	Momelotinib (CYT387) corrected hematocrit, spleen size, white blood cell count, and physiological levels of inflammatory cytokines in a mouse model of MPN [3].
Animal Protocol	Dissolved in NMP (120 mg/mL final; 1-methyl-2-pyrrolidinone, Chromasolv Plus). Subsequently, the CYT387/NMP mix is diluted with 0.14 M Captisol to a concentration of 6 mg/mL and further diluted with 0.1M Captisol to a final concentration of 4 mg; 50 mg daily; Oral gavage Balb/c mice are transplanted with bone marrow transduced with a JAK2V617F retrovirus.
ADME/Pharmacokinetics	Absorption, Distribution and Excretion Momelotinib is rapidly absorbed following oral administration with a bioavailability of 97%. The mean (%CV) steady-state Cmax is 479 ng/mL (61%), and the mean (%CV) AUC is 3,288 ng x h/mL (60%) at the maximum recommended dosage. Momelotinib exposure (i.e., Cmax and AUC) increases dose proportionally from 100 mg to 300 mg (0.5 to 1.5 times the maximum recommended dosage), but less than dose-proportional at doses from 400 mg to 800 mg (two to four times the maximum recommended dosage). There is no clinically significant accumulation. The Tmax at steady state is two hours (Q1: 1 hour; Q3: 3 hours) post-dose. No clinically significant differences in momelotinib pharmacokinetics were observed following administration of either a high-fat meal (800 kcal; 50% fat) or low-fat meal (400 kcal; 20% fat) in healthy subjects. Momelotinib is primarily eliminated in feces and, to a lesser extent, in urine. Following a single oral dose of radiolabeled momelotinib in healthy subjects, about 69% of the total radioactive dose was recovered in fecesm with M14 accounting for 21.4% of the dose, momelotinib and M21 each accounting for 13%, and other 12 metabolites accounting for the remaining 22%. About 28% of radioactivity was recovered in urine, with M21 being the major species. The mean (%CV) apparent volume of distribution at steady-state is 984 L (118%). The mean (%CV) clearance is clearance is 103 L/h (87%). Metabolism / Metabolites Momelotinib is metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP3A4 (36%), CYP2C8 (19%), CYP2C9 (17%), CYP2C19 (19%), and CYP1A2 (9%). M21 is initially formed via oxidation of the morpholine ring by the same CYP enzymes, followed by metabolism via aldehyde oxidase. M21 is a major metabolite in humans that retains approximately 40% of the pharmacological activity of the parent. The mean ratio of M21 to momelotinib for AUC ranged from 1.4 to 2.1. Momelotinib can undergo amide hydrolysis, N-dealkylation, nitrile hydrolysis, nitrile oxidation, and glucuronidation. Biological Half-Life The elimination half-life of momelotinib and the M21 metabolite is four to eight hours.
Toxicity/Toxicokinetics	Hepatotoxicity In the published preregistration clinical trials of momelotinib, rates of serum ALT or AST elevations ranged from 21% to 31% and were above 5 times the upper limit of normal (ULN) in 0.5% to 2.0%, and above 20 times ULN in 0.5%. Two of 448 momelotinib treated patients evaluated in the safety cohort developed clinically apparent, but self-limiting liver injury with jaundice. A third patient developed liver injury with jaundice that appeared to be due to reactivation of hepatitis B. The liver injury was typically hepatocellular without immune allergic or autoimmune features, arising after 2 to 4 months of therapy, and resolving soon after drug discontinuation. Peak ALT elevations ranged from 308 to 1178 U/L and peak bilirubin from 2.3 to 7.0 mg/dL. There were no deaths from hepatic failure. Since its approval and more widespread clinical use, there have been no further reports of serum enzyme or bilirubin elevations or instances of clinically apparent liver injury, but it has been available for a limited time only. Likelihood score: D (possible cause of clinically apparent liver injury including reactivation of hepatitis B). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of momelotinib during breastfeeding. Because momelotinib is 91% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during momelotinib therapy and for at least 1 week after the last dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Momelotinib is 91% bound to plasma proteins in healthy volunteers.
References	[1]. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia, 2009, 23(8), 1441-1445. [2]. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia, 2011, 25(12), 1891-1899. [3]. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood, 2010, 115(25), 5232-5240. [4]. Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS.Cancer Cell. 2018 Sep 10;34(3):439-452.e6.
Additional Infomation	Pharmacodynamics Momelotinib inhibits Janus Kinase 1 and 2 (JAK1/JAK2) with an IC50 of 11 and 18 nM, respectively. It also inhibits JAK3 (IC50 = 155 nM) and tyrosine kinase 2 (TYK2) (IC50 = 17 nM) with less selectivity. Momelotinib inhibited STAT3 phosphorylation in whole blood from patients with myelofibrosis (MF). Maximal inhibition of STAT3 phosphorylation occurred two hours after momelotinib dosing, which persisted for at least six hours. Iron availability and erythropoiesis were assessed by analysis of circulating hepcidin concentrations: an acute and sustained reduction of circulating hepcidin was observed for the duration of the 24-week administration of momelotinib to patients with MF.

Solubility Data

Solubility (In Vitro)

DMSO: 74 mg/mL (178.5 mM) Water:<1 mg/mL Ethanol:<1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.4128 mL	12.0639 mL	24.1278 mL
	5 mM	0.4826 mL	2.4128 mL	4.8256 mL
	10 mM	0.2413 mL	1.2064 mL	2.4128 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.