Synthesis, biological evaluation and docking studies of new pyrrolo[2,3-d] pyrimidine derivatives as Src family-selective tyrosine kinase inhibitors

Figures & data

Figure 1.  Pyrazolopyrimidine and pyrrolopyrimidine derivatives as SFK inhibitors.

Scheme 1.  Synthesis of pyrrolo[2,3-d]pyrimidine amide derivatives.

Table 1.  Inhibition of SFKs (c-Src, Fyn and Lyn) by compounds 5–8 and reference compounds.

		% c-Src inhibition^b			% Fyn inhibition^b			% Lyn inhibition^b
Comp. No	IC50 values^a	0.1	0.01	0.001	0.1	0.01	0.001	0.1	0.01	0.001
		mM	mM	mM	mM	mM	mM	mM	mM	mM
5		54 ± 4	50 ± 4	50 ± 1 (21 µM)^c	38 ± 4	35 ± 2	32 ± 1	32 ± 1	25 ± 1	17 ± 2
6		14 ± 4	4 ± 4	25 ± 2	46 ± 3	30 ± 4	28 ± 5	42 ± 4	16 ± 2	12 ± 2
7		71 ± 2	53 ± 6 (16 µM)^c	39 ± 2	41 ± 0	33 ± 5	28 ± 2	40 ± 1	21 ± 3	12 ± 3
8		60 ± 1	50 ± 2	40 ± 6	36 ± 3	31 ± 8	18 ± 0	28 ± 1	20 ± 1	13 ± 2
PP2	0.5 nM (Fyn)
A-419259	0.3 nM (Lyn)
CGP77675	0.4 nM (c-Src)

^aActivity data of reference compounds were calculated as nM level.

^bAverage (from three independent experiments) % inhibitory effects of compounds at 0.1, 0.01 and 0.001 mM concentrations.

^cIC₅₀ values of compounds were given as µM level.

Figure 2.  The inhibitory effect of the molecules at 0.1, 0.01 and 0.001 mM concentrations on Fyn activity.

Figure 3.  The inhibitory effect of the molecules at 0.1, 0.01 and 0.001 mM concentrations on Lyn activity.

Figure 4.  The inhibitory effect of the molecules at 0.1, 0.01 and 0.001 mM concentrations on c-Src activity.

Figure 5.  (A) Comparison of compound 5 and PP2 (orange) with Fyn binding site; (B) Comparison of compound 5 and CGP77675 (green) with c-Src binding site.