KB-0742 dihydrochloride (KB0742)

Description

APIM050402: KB-0742 dihydrochloride (KB0742), is an orally bioavailable, potent and selective CDK9 inhibitor with an IC₅₀ of 6 nM, highly selective against other CDKs (>60 fold).

CAS No.: 2416874-75-2
IUPAC/Chemical Name: (R)-1-cyanobutan-2-yl ((S)-1-(3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)phenyl)ethyl)carbamate
Molecular Formula: C₁₆H₂₅N₅•2HCl
Molecular Weight: 360.3
Purity: >99% pure by Achiral and Chiral HPLCs
QC: Achiral and Chiral HPLCs, MS, NMR, and Quantitative Elemental Analysis Report
Solubility: Soluble in Water (>18.6mg/ml, >50mM)
Storage: Store at 0 oC (short term), at -20 oC (long term), desiccated in a tightly
closed container. (Caution: Very Hygroscopic)
Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

KB-0742 dihydrochloride (CAS No: 2416874-75-2) is a potent, selective and orally active CDK9 inhibitor with an IC5₅₀ of 6 nM for CDK9/cyclin T1. KB-0742 dihydrochloride is selective for CDK9/cyclin T1 with >50-fold selectivity over other CDK kinases. KB-0742 dihydrochloride has potent anti-tumor activity.[1]

KB-0742 showed selectivity for CDK9 over other CDK family members, downregulated AR-dependent oncogenic transcription, and reduced tumor cell growth and promoted apoptosis in in vitro. Additionally, oral administration of KB-0742 (administered as a 3-day on/4-day off regimen) to mice that had been engrafted with castration resistant prostate cancer cells significantly inhibited tumor growth with modest effects on body weight. In a subsequent mouse xenograft study using a MYC-dependent acute myeloid leukemia model, KB-0742 administration again resulted in significant tumor growth inhibition with dose-dependent effects on pharmacodynamic markers of CDK9 inhibition in tumor. [2]

Target: CDK9/cyclinT1

IC₅₀: 6 nM

In Vitro: KB-0742 (6 hours; 0.1-10 μM; 22Rv1 cells) treatment significant reduction of downstream phosphorylation of RNA Pol II at Ser2 and Ser7, and diminished phosphorylation at Ser5. Global androgen receptor (AR)-FL and AR-V protein levels are significantly reduced starting at 6 h treatment time, which is accompanied by the reduction of phospho-AR levels (Ser81).[1]
KB-0742 (48-72 hours) treatment shows cytostatic effects in prostate cancer and leukemia cell lines. KB-0742 shows antiproliferative activity with GR50s of 0.183 μM and 0.288 μM for 22Rv1 cells and MV-4-11 AML cells, respectively.[1]
In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs.[1]

In Vivo: KB-0742 (3-30 mg/kg; p.o.; daily; over 21 days) is well tolerated even at high dose, while significantly reducing tumor burden in 22Rv1 human prostate cancer cell line-derived xenograft (CDX) models.[1]

What is the solubility of KB0742 in vitro?
H2O: 100 mg/mL (277.52 mM; Need ultrasonic); DMSO: 62.5 mg/mL (173.45 mM; Need ultrasonic)

What is the solubility of KB0742 in vivo?
1. Solvent: DMSO, PEG300, Tween-80, and saline
Please add 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline in order; solubility ≥ 2.08mg/mL.
2. DMSO and 20% SBE-β-CD in salin
Please add 10% DMSO and 90% (20% SBE-β-CD in saline) in order; solubility 2.08 mg/mL (need ultrasonic).
3. DMSO and corn oil
Please add 0% DMSO and 90% corn oil in order, solubility ≥ 2.08 mg/mL.

Reference:
[1]. Richters, A. et al. “Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors”, Cell Chem. Biol., 2021, 28, 134-147
[2]. Kronos Bio “A Dose Escalation and Cohort Expansion Study of KB-0742 in Participants With Relapsed or Refractory Solid Tumors or Non-Hodgkin Lymphoma”, ClinicalTrials.gov Identifier: NCT04718675.
[3]. Day, M. A. et al. “Abstract 1141: CDK9 inhibition is selective for transcriptionally addicted tumors harboring MYC genomic amplifications”, Cancer Res. 2021, DOI: 10.1158/1538-7445.AM2021-1141.

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Additional information

Size	10 mg, 100 mg, 5 mg, 50 mg

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