Emavusertib (CA-4948) is a first-in-class, orally bioactive and highly potent IRAK4/FLT3 inhibtor (IC50 of < 50 nM) with anticancer activity. CA4948 is currently undergoing testing in a Phase 1 trial in patients with non-Hodgkin's lymphoma and in a Phase 1 trial in patients with acute myeloid leukemia and myelodysplastic syndromes.

Physicochemical Properties

Molecular Formula	C24H25N7O5
Molecular Weight	491.499204397202
Exact Mass	491.19
Elemental Analysis	C, 58.65; H, 5.13; N, 19.95; O, 16.28
CAS #	1801344-14-8
Related CAS #	Emavusertib hydrochloride;2376399-42-5
PubChem CID	118224491
Appearance	Light yellow to green yellow solid powder
LogP	1.7
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	5
Heavy Atom Count	36
Complexity	773
Defined Atom Stereocenter Count	1
SMILES	CC1=NC=CC(=C1)C2=NC(=CO2)C(=O)NC3=CC4=C(N=C3N5CC[C@H](C5)O)N=C(O4)N6CCOCC6
InChi Key	SJHNWSAWWOAWJH-MRXNPFEDSA-N
InChi Code	InChI=1S/C24H25N7O5/c1-14-10-15(2-4-25-14)23-27-18(13-35-23)22(33)26-17-11-19-20(28-21(17)31-5-3-16(32)12-31)29-24(36-19)30-6-8-34-9-7-30/h2,4,10-11,13,16,32H,3,5-9,12H2,1H3,(H,26,33)/t16-/m1/s1
Chemical Name	(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
Synonyms	CA4948 Emavusertib CA 4948 CA-4948
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	IRAK4:50 nM (IC50)
ln Vitro	When compared to IRAK-1, emavusertib (CA-4948) exhibits an over 500-fold selectivity for IRAK-4. With an IC50 of less than 250 nM, emavusertib decreases the release of TNF-α, IL-1β, IL-6, and IL-8 from TLR-stimulated THP-1 cells. Because emavusertib inhibits the receptor-type casein inhibitor FLT3, it still has binding antiproliferative action [1]. Emavusertib binds to IRAK-4 more strongly than it does to IRAK 1, 2, and 3. In marginal zone quiescent zone (MZL) cell lines, emavusertib (10 μM, 72 h) decreases the total number of proliferating cells and increases sub-G0 fractional motility [3]. Emavusertib (10 μM, 72 h) exhibits efficacy greater than 350 times [3]. can cause a noticeable rise in the quantity of MZL cells, particularly when taken in conjunction with Ibrutinib [3].
ln Vivo	In animal models, emavusertib (CA-4948) has shown anticancer efficacy against cancers with mutations in the MyD88 gene. In FLT3 wild-type and FLT3 mutant acute myeloid leukemia (AML) animal models, emavusertib exhibits antileukemic action [1]. Emavusertib can decrease tumor growth in mice when given orally, once daily, for 14 days at a dose of 25–150 mg/kg [3].
Animal Protocol	Animal/Disease Models: Mice bearing OCI-LY10 tumors[3] Doses: 25, 50, or 150 mg/kg (one time/day), 12.5, 25, or 50 mg/kg (twice (two times) daily) Route of Administration: Orally, one time/day or twice (two times) daily , for 14 days Experimental Results: Induced tumor growth inhibition. Emavusertib administered as a twice-daily divided dose was equivalent to the corresponding once-daily dose with regards to antitumor activity, ie, 12.5 mg/kg BID versus 25 mg/kg QD.
References	[1]. Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs. 2020 Apr 17:1-8. [2]. Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors. J Clin Med. 2023 Jan 4;12(2):399. [3]. IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies. Front Immunol. 2023 Oct 26;14:1239082.
Additional Infomation	Emavusertib is an orally bioavailable, reversible inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), with potential antineoplastic, immunomodulating and anti-inflammatory activities. Upon oral administration, emavusertib targets, binds to, and blocks the kinase activity of IRAK4. This inhibits IRAK4-mediated signaling, prevents the activation of IRAK4-mediated nuclear factor-kappa B (NF-kB) signaling and decreases the expression of inflammatory cytokines and certain pro-survival factors. This inhibits proliferation of IRAK4-overactivated tumor cells, which are found in cells harboring MYD88 activating mutations or those with overactivated toll-like receptor (TLR) pathways. In addition, CA-4948 may inhibit inflammation and immune-mediated cell destruction in inflammatory and auto-immune diseases where TLR or interleukin 1 receptor (IL-1R) signaling is overactivated and MYD88 is dysregulated. IRAK4, a serine/threonine-protein kinase that plays a key role in both the TLR and IL-1R signaling pathways, is activated though the adaptor protein MYD88 and links the TLR and IL-1R signaling pathway to the NF-kB pathway.

Solubility Data

Solubility (In Vitro)

DMSO : ~50 mg/mL (~101.73 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.23 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 20.8 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: 2.08 mg/mL (4.23 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.0346 mL	10.1729 mL	20.3459 mL
	5 mM	0.4069 mL	2.0346 mL	4.0692 mL
	10 mM	0.2035 mL	1.0173 mL	2.0346 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.