Cell lines

CHO and GIST cells

Preparation method

Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reaction Conditions

43 ~ 106 nM for CHO cells, 2 ~ 32 nM for GIST cells

Applications

In CHO cells, DCC-2618 inhibited resistant Exon 17 KIT mutations with the IC50 values ranging from 43 to 106 nM. In GIST cells, DCC-2618 inhibited mutant KIT with the IC50 values ranging from 2 to 32 nM.

Animal models

GIST xenografts

Dosage form

25 and 50 mg/kg; p.o.

Applications

DCC-2618 inhibited KIT in GIST xenografts after single dose. At the doses of 25 and 50 mg/kg, DCC-2618 showed promising potency on pKIT (Y703) with the inhibition ranging from 39% to 79% 2 ~ 12 hrs after the administration.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

IC50: 6 nM, 9 nM, 18 nM, 5 nM, 14 nM and 9 nM for wt c-KIT, KIT V654A, KIT T670I, KIT D816H, KIT D816V and KIT JMD ΔVV/D816V, respectively.

DCC-2618 is a small-molecule inhibitor of KIT kinases.

Gastrointestinal stromal tumors (GIST) are driven by gain-of-function mutations of the KIT (approx 90%) or PDGFR (approx 10%) receptor tyrosine kinases. DCC-2618 has been designed to effectively inhibit the imatinib and sunitinib-sensitive KIT juxtamenbrane domin mutants as well as secondary resistant KIT iniase-domain mutants.

In vitro: DCC-2618 is a kinase switch inhibitor that can control drug resistant mutants of KIT and PDGFR in GIST. DCC-2618 acts by imposing an inactive conformation (shape) of highly resistant and aggressive secondary mutations of KIT kinase [1].

In vivo: DCC-2618 inhibits KIT in GIST tumor xenografts after single dose. At the doses of 50 and 25 mpk, DCC-2618 showed promising potency on pKIT (Y703) with the inhibition ranging from 39% to 79% 2-12 hrs after the administration [1].

Clinical trial: A Phase I trial with refractory GIST patients is planned.

Reference:
[1] DCC-2618, a small molecule inhibitor of normal and mutant KIT kinasefor treatment of refractory gastrointestinal stromal tumors (GIST)Deciphera Pharmaceuticals, Lawrence, KS.