Mevociclib (formerly SY-1365; SY1365) is a novel, potent, highly selective and covalent/irreversible inhibitor of CDK7 (Cyclin-dependent kinase 7) with anticancer activity. SY-1365 has the potential to be used therapeutically for solid and hematological tumors. At nanomolar concentrations, SY-1365 inhibited the growth of numerous cancer types' cells in vitro. MCL1 protein levels were reduced by SY-1365 treatment, and it was discovered that cancer cells that expressed less BCL2L1 (BCL-XL) were more susceptible to SY-1365. Acute myeloid leukemia (AML) cell lines showed different transcriptional alterations after treatment with other transcriptional inhibitors. As a single agent, SY-1365 showed significant antitumor effects in several AML xenograft models; when combined with the BCL2 inhibitor venetoclax, SY-1365-induced growth inhibition was amplified. Additionally, xenograft models of ovarian cancer showed antitumor activity, indicating that SY-1365 may be investigated in the clinic for solid and hematologic tumors alike. Our results validate CDK7 targeting as a novel therapeutic strategy for transcriptionally driven cancers.

Physicochemical Properties

Molecular Formula	C31H35CLN8O2
Molecular Weight	587.115004777908
Exact Mass	586.26
Elemental Analysis	C, 63.42; H, 6.01; Cl, 6.04; N, 19.09; O, 5.45
CAS #	1816989-16-8
Related CAS #	1816989-16-8;Mevociclib mesylate; Mevociclib HCl;
PubChem CID	118426108
Appearance	White to off-white solid powder
LogP	4.2
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	9
Heavy Atom Count	42
Complexity	952
Defined Atom Stereocenter Count	2
SMILES	C[C@@]1(CCC[C@H](C1)NC2=NC=C(C(=N2)C3=CNC4=CC=CC=C43)Cl)NC(=O)C5=NC=C(C=C5)NC(=O)/C=C/CN(C)C
InChi Key	SCJNYBYSTCRPAO-LXBQGUBHSA-N
InChi Code	InChI=1S/C31H35ClN8O2/c1-31(39-29(42)26-13-12-21(17-33-26)36-27(41)11-7-15-40(2)3)14-6-8-20(16-31)37-30-35-19-24(32)28(38-30)23-18-34-25-10-5-4-9-22(23)25/h4-5,7,9-13,17-20,34H,6,8,14-16H2,1-3H3,(H,36,41)(H,39,42)(H,35,37,38)/b11-7+/t20-,31+/m1/s1
Chemical Name	N-[(1S,3R)-3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-1-methylcyclohexyl]-5-[[(E)-4-(dimethylamino)but-2-enoyl]amino]pyridine-2-carboxamide
Synonyms	SY-1365; SY 1365; SY1365
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	CDK7
ln Vitro	Mevociclib has an IC50 of 20 nM for CDK7/CycH/MAT1 inhibition[2]. Mevociclib, a highly selective covalent CDK7, has no effect on non-growing cells but causes cell cooling in albino cells [2]. Mevociclib exhibits action in colorectal, lung, breast, and ovarian cancer cells; these cells display low nM EC50 and fast cellular fluorescence induction [2].
ln Vivo	In an in vivo TNBC tumor model, mevociclib (20 mg/kg; iv; biw; for 35 days) suppresses growth [2]. A distinct transcriptional signature is induced by mevociclib [2].
Animal Protocol	Animal/Disease Models: Mouse, HCC70 xenograft model [2] Doses: 20 mg/kg Route of Administration: intravenous (iv) (iv)injection, twice a week for 35 days Experimental Results: Inhibition of tumor volume in vivo.
References	[1]. Discovery and characterization of SY-1365, a selective, covalent inhibitor of CDK7. Cancer Res. 2019 May 7. [2]. SY-1365, a potent and selective CDK7 inhibitor, exhibits promising anti-tumor activity in multiple preclinical models of aggressive solid tumors.
Additional Infomation	Mevociclib (SY-1365) is a selective CDK7 inhibitor. Mevociclib exhibits anti-proliferative and apoptotic effects in solid tumor cell lines. Mevociclib possesses anti-tumor activity in hematological and multiple aggressive solid tumors. Mevociclib is a selective inhibitor of cyclin-dependent kinase 7 (CDK7), with potential antineoplastic activity. Upon administration, SY-1365 binds to and inhibits CDK7, thereby inhibiting CDK7-mediated signal transduction pathways. This inhibits cell growth of CDK7-overexpressing tumor cells. CDK7, a serine/threonine kinase, plays a key role in cell proliferation; CDK7 is overexpressed in a variety of tumor cell types.

Solubility Data

Solubility (In Vitro)

DMSO: ~125 mg/mL (~212.9 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.54 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 (3.54 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	1.7032 mL	8.5161 mL	17.0323 mL
	5 mM	0.3406 mL	1.7032 mL	3.4065 mL
	10 mM	0.1703 mL	0.8516 mL	1.7032 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.