Serdemetan (formerly JNJ26854165; JNJ-26854165; JNJ 26854165) which was initially created as a p53 activator, is now thought to be a brand-new, powerful, and orally bioactive HDM-2 ubiquitin ligase antagonist with antitumor properties. Additionally, it causes cellular proliferation inhibition and delayed apoptosis in the absence of functional p53. It also causes early apoptosis in p53 wild-type cells.

Physicochemical Properties

Molecular Formula	C21H20N4
Molecular Weight	328.41
Exact Mass	328.168
Elemental Analysis	C, 76.80; H, 6.14; N, 17.06
CAS #	881202-45-5
Related CAS #	881202-45-5
PubChem CID	11609586
Appearance	white solid powder
Density	1.3±0.1 g/cm3
Boiling Point	615.1±50.0 °C at 760 mmHg
Flash Point	325.8±30.1 °C
Vapour Pressure	0.0±1.8 mmHg at 25°C
Index of Refraction	1.747
LogP	3.45
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	3
Rotatable Bond Count	6
Heavy Atom Count	25
Complexity	387
Defined Atom Stereocenter Count	0
SMILES	N1C=CC(NC2C=CC(NCCC3C4C(=CC=CC=4)NC=3)=CC=2)=CC=1
InChi Key	CEGSUKYESLWKJP-UHFFFAOYSA-N
InChi Code	InChI=1S/C21H20N4/c1-2-4-21-20(3-1)16(15-24-21)9-14-23-17-5-7-18(8-6-17)25-19-10-12-22-13-11-19/h1-8,10-13,15,23-24H,9,14H2,(H,22,25)
Chemical Name	1-N-[2-(1H-indol-3-yl)ethyl]-4-N-pyridin-4-ylbenzene-1,4-diamine
Synonyms	Serdemetan; JNJ26854165; JNJ-26854165; JNJ 26854165
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	p53; HDM2; Mdm2
ln Vitro	JNJ 26854165 is a novel tryptamine derivative which activates p53 and acts as a HDM2 ubiquitin ligase antagonist. JNJ 26854165 inhibits cell growth and triggers apoptosis in leukemia cell lines, with IC50 values for OCI-AML-3, MOLM-13, NALM-6, and REH cells being 0.24, 0.33, 0.32, and 0.44 M at 72 hours, respectively. JNJ 26854165 also counteracts the transcriptional induction of p21 by p53 and speeds up the proteasome-mediated degradation of p21. Additionally, it delays S-phase and increases the expression of E2F1 in p53 mutant cells, which favors the apoptosis of S-phase cells.[1] JNJ 26854165 is an oral Mdm2 inhibitor that binds to Mdm2's RING domain to prevent the Mdm2-p53 complex from interacting with the proteasome and raise p53 levels.[2]
ln Vivo	JNJ 26854165 causes statistically significant differences in the EFS distribution in 5 of 7 (71%) and 17 of 36 (47%) of the evaluable ALL xenografts and 17 of 36 (47%) of the evaluable solid tumor xenografts, respectively. [4]
Cell Assay	Fetal calf serum (FCS), which has been heat-inactivated to 10%, is used to maintain cell lines in RPMI 1640 medium. OCI-AML-3, MOLM-13, NB4, and U937 cells come from AML patients, K562 from a CML patient going through a blast crisis, and NALM-6, REH, and P12-ICHIK cells come from patients with chronic myelogenous leukemia.
Animal Protocol	CB17SC scid-/- female mice. ≤20 mg/kg Administered via p.o.
References	[1]. Mol Cancer Ther . 2010 May;9(5):1158-68. [2]. Cancer Lett . 2011 Dec 22;312(2):209-18. [3]. Pediatr Blood Cancer . 2012 Aug;59(2):329-32. [4]. Pediatr Blood Cancer, 2012, 59(2), 329-332.
Additional Infomation	Serdemetan has been used in trials studying the treatment of Neoplasms. Serdemetan is an orally bioavailable HDM2 antagonist with potential antineoplastic activity. Serdemetan inhibits the binding of the HDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this HDM2-p53 interaction, the proteasome-mediated enzymatic degradation of p53 is inhibited, which may result in the restoration of p53 signaling and thus the p53-mediated induction of tumor cell apoptosis. HDM2 (human homolog of double minute 2), a zinc finger protein, is a negative regulator of the p53 pathway; often overexpressed in cancer cells, it has been implicated in cancer cell proliferation and survival.

Solubility Data

Solubility (In Vitro)

DMSO: ~66 mg/mL (~201 mM) Water: <1 mg/mL (slightly soluble or insoluble) Ethanol: ~2 mg/mL (~6.1 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.61 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: ≥ 2.5 mg/mL (7.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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: ≥ 2.5 mg/mL (7.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension 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 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 30 mg/mL  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.0450 mL	15.2249 mL	30.4497 mL
	5 mM	0.6090 mL	3.0450 mL	6.0899 mL
	10 mM	0.3045 mL	1.5225 mL	3.0450 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.