Safimaltib (JNJ-67856633) is an orally bioactive, Class I, specific and allosteric MALT1 protease inhibitor. Safimaltib caused tumor stasis in some cases.

Physicochemical Properties

Molecular Formula	C20H11F6N5O2
Molecular Weight	467.324064493179
Exact Mass	467.081
CAS #	2230273-76-2
PubChem CID	134609793
Appearance	Off-white to yellow solid powder
LogP	2.9
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	3
Heavy Atom Count	33
Complexity	788
Defined Atom Stereocenter Count	0
SMILES	FC(C1=C(C(NC2C=CN=C(C(F)(F)F)C=2)=O)C=NN1C1=CC=CC2C(NC=CC1=2)=O)(F)F
InChi Key	APWRZPQBPCAXFP-UHFFFAOYSA-N
InChi Code	InChI=1S/C20H11F6N5O2/c21-19(22,23)15-8-10(4-6-27-15)30-18(33)13-9-29-31(16(13)20(24,25)26)14-3-1-2-12-11(14)5-7-28-17(12)32/h1-9H,(H,28,32)(H,27,30,33)
Chemical Name	1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide
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	MALT1 protease[1][2][3]
ln Vitro	In both mouse and rat tumors, safimaltib (JNJ-67856633) is efficient and highly bioavailable, sometimes resulting in tumor stasis. According to serum IL10 levels or uncleaved BCL10 levels in tumors, safimaltib produced a strong in vivo pharmacodynamic shutdown in both CD79b- and CARD11-mutant ABC-models of DLBCL [1][3].
ln Vivo	JNJ-67856633 administration was associated with a dose-dependent decrease of Tregs (CD4+CD25+FoxP3+) generation following CD3/28 activation, which shows that MALT1 inhibition may have an immunomodulatory effect [3].
References	[1]. Virtual meeting delivers first time drug structures. [2]. A Phase 1, First-in-Human, Open-Label Study of the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-67856633, an Inhibitor of MALT1, in Participants with NHL and CLL. [3]. Abstract 5690: Discovery of JNJ-67856633: A novel, first-in-class MALT1 protease inhibitor for the treatment of B cell lymphomas.
Additional Infomation	Safimaltib is an orally bioavailable inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), with potential antineoplastic activity. Upon administration, safimaltib targets, binds to, and prevents the activity of MALT1. This inhibits MALT1-dependent signaling, reduces interleukin-10 (IL-10) and upregulates interferon (IFN). This results in the inhibition of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling and nuclear factor-kappa B (NF-kB) signaling, induces apoptosis, and inhibits tumor cell growth of MALT1-expressing tumor cells. MALT1 belongs to the caspase family of proteases and is the active component of the CARD11-BCL10-MALT1 (CBM) signaling complex. It plays an essential role in B- and T-lymphocyte activation and is over-activated in certain tumor cells.

Solubility Data

Solubility (In Vitro)

DMSO: 125 mg/mL (267.48 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.45 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 (4.45 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 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 (4.45 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	2.1399 mL	10.6993 mL	21.3986 mL
	5 mM	0.4280 mL	2.1399 mL	4.2797 mL
	10 mM	0.2140 mL	1.0699 mL	2.1399 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.