OTS964 HCl | CAS#1338545-07-5 | TOPK inhibitor

MedKoo Cat#: 206191 | Name: OTS964 HCl

Description:

WARNING: This product is for research use only, not for human or veterinary use.

OTS964 is a potent and selective TOPK inhibitor with potential anticancer activity. OTS964 inhibits TOPK kinase activity with high affinity and selectivity. Similar to the knockdown effect of TOPK small interfering RNAs (siRNAs), this inhibitor causes a cytokinesis defect and the subsequent apoptosis of cancer cells in vitro as well as in xenograft models of human lung cancer. Although administration of the free compound induced hematopoietic adverse reactions (leukocytopenia associated with thrombocytosis), the drug delivered in a liposomal formulation effectively caused complete regression of transplanted tumors without showing any adverse reactions in mice. ( Sci Transl Med. 2014 Oct 22;6(259):259ra145. )

Chemical Structure

OTS964 HCl

CAS#1338545-07-5 (HCl)

Theoretical Analysis

MedKoo Cat#: 206191

Name: OTS964 HCl

CAS#: 1338545-07-5 (HCl)

Chemical Formula: 23H25ClN2O2S

Exact Mass: 0.0000

Molecular Weight: 428.98

Elemental Analysis: C, 64.40; H, 5.87; Cl, 8.26; N, 6.53; O, 7.46; S, 7.47

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship

Bulk Inquiry

Buy Now

Add to Cart

Related CAS #

1338542-14-5 (free base) 1338545-07-5 (HCl)

Synonym

OTS964; OTS964; OTS 964; OTS964 HCl; OTS964 hydrochloride

IUPAC/Chemical Name

(R)-9-(4-(1-(dimethylamino)propan-2-yl)phenyl)-8-hydroxy-6-methylthieno[2,3-c]quinolin-4(5H)-one hydrochloride

InChi Key

YHPWOYBWUWSJDW-UQKRIMTDSA-N

InChi Code

InChI=1S/C23H24N2O2S.ClH/c1-13-11-18(26)19(16-7-5-15(6-8-16)14(2)12-25(3)4)20-17-9-10-28-22(17)23(27)24-21(13)20;/h5-11,14,26H,12H2,1-4H3,(H,24,27);1H/t14-;/m0./s1

SMILES Code

[H]Cl.O=C1NC2=C(C(C3=CC=C([C@@H](C)CN(C)C)C=C3)=C(O)C=C2C)C4=C1SC=C4

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>5 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A20T11K18

View CoA: current batch, Lot#B21B08C24

QC Data

View QC data: current batch, Lot#B21B08C24

View QC data: current batch, Lot#A20T11K18

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

OTS964 hydrochloride is a TOPK (T-lymphokine-activated killer cell-originated protein kinase) inhibitor with an IC50 of 28 nM. OTS964 hydrochloride is also a potent inhibitor of the cyclin-dependent kinase CDK11, which binds to CDK11B with a Kd of 40 nM.

In vitro activity:

This study next determined the cellular effects of OTS964 treatment and CDK11 ablation with CRISPR. In cell competition assays, cancer cells transduced with guide RNAs specific for either CDK11A or CDK11B exhibited minimal dropout. However, guides designed to recognize both isoforms exhibited substantial dropout in every cell line that was tested, including pancreatic cancer and triple-negative breast cancer (Fig. 4G and fig. S17A). Flow cytometry revealed that cells transduced with pan-CDK11 guides accumulated in G2/M with 4C DNA content, suggesting that CDK11 function is required for mitotic progression (fig. S17B). To test whether OTS964 phenocopied the CDK11 guide RNAs, this study arrested A375 cells expressing the chromosomal marker H2B-mCherry at G1/S with a double-thymidine block, and then released them into normal medium or medium containing OTS964. Cells treated with a low concentration of OTS964 exhibited delayed nuclear envelope breakdown and progressed slowly through mitosis (Fig. 4H, fig. S17C, and movies S1–2). Cells treated with a lethal concentration of OTS964 arrested in G2, before mitotic entry (movie S3). OTS964 treatment did not perturb DNA replication, as the arrested cells displayed 4C DNA content and did not accumulate 53BP1-foci, a marker of DNA damage (fig. S17D–E). Introducing the G579S substitution into A375 cells rescued normal mitotic entry and progression in the presence of a lethal concentration of OTS964 (fig. 4H–I, fig. S17C, and movie S4). These results establish CDK11 activity as necessary for mitosis in human cancer and suggest that CDK11 is the key in cellulo target of OTS964. Reference: Sci Transl Med. 2019 Sep 11; 11(509): eaaw8412. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717492/

In vivo activity:

When this study administered free OTS964 intravenously at 40 mg/kg on days 1, 4, 8, 11, 15, and 18 to mice bearing LU-99 lung cancer cells, this study observed a TGI of 44% on day 22 (Fig. 4A) without any body weight loss (Fig. 4B). Similar to observation with OTS514, OTS964 treatment also enhanced the differentiation of HSCs to a megakaryocyte population (fig. S7A). Furthermore, both compounds resulted in a reduction of STAT5 (signal transducer and activator of transcription 5) protein (fig. S7B). When this study administered liposomal OTS964 at 40 mg/kg on days 1, 4, 8, 11, and 15 to mice bearing LU-99 lung cancer cells after the tumor size reached about 150 mm3 (instead of 200 mm3 as in Fig. 4A, to allow longer monitoring of the rapidly growing LU-99 tumors; see Materials and Methods for details), this study observed a TGI of 110% on day 22. The tumors continued shrinking even after the treatment and finally revealed complete regression in five of six mice examined (three mice on day 25 and two mice on day 29) (Fig. 4C) without any body weight loss (Fig. 4D). Most strikingly, this liposomal formulation did not cause any hematopoietic toxicity (Fig. 4E). Further preclinical toxicity studies in rats did not show any histopathological changes in the liver after treatment with liposomal OTS964 (fig. S8). Reference: Sci Transl Med. 2014 Oct 22;6(259):259ra145. https://pubmed.ncbi.nlm.nih.gov/25338756/

	Solvent	mg/mL	mM
Solubility
	DMSO	30.0	69.90

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 428.98 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, Sausville EL, Lukow DA, Liu L, Chait AR, Galluzzo ZC, Tucker C, Sheltzer JM. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med. 2019 Sep 11;11(509):eaaw8412. doi: 10.1126/scitranslmed.aaw8412. PMID: 31511426; PMCID: PMC7717492. 2. Sugimori M, Hayakawa Y, Koh M, Hayashi T, Tamura R, Kuroda S. Targeting the T-Lak cell originated protein kinase by OTS964 shrinks the size of power-law coded heterogeneous glioma stem cell populations. Oncotarget. 2017 Dec 9;9(3):3043-3059. doi: 10.18632/oncotarget.23077. PMID: 29423027; PMCID: PMC5790444. 3. Matsuo Y, Park JH, Miyamoto T, Yamamoto S, Hisada S, Alachkar H, Nakamura Y. TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis. Sci Transl Med. 2014 Oct 22;6(259):259ra145. doi: 10.1126/scitranslmed.3010277. PMID: 25338756.

In vitro protocol:

In vivo protocol:

1. Matsuo Y, Park JH, Miyamoto T, Yamamoto S, Hisada S, Alachkar H, Nakamura Y. TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis. Sci Transl Med. 2014 Oct 22;6(259):259ra145. doi: 10.1126/scitranslmed.3010277. PMID: 25338756.

1: Novel molecule targets cytokinesis. Cancer Discov. 2015 Jan;5(1):OF8. doi: 10.1158/2159-8290.CD-NB2014-170. Epub 2014 Nov 13. PubMed PMID: 25583820. 2: Matsuo Y, Park JH, Miyamoto T, Yamamoto S, Hisada S, Alachkar H, Nakamura Y. TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis. Sci Transl Med. 2014 Oct 22;6(259):259ra145. doi: 10.1126/scitranslmed.3010277. PubMed PMID: 25338756.