Table 3.

Summary of pharmacological profiles

Comparison of signaling (maximal efficacy of activation of Akt/Erk in RET-expressing cells) by the compounds relative to each other and to GDNF. Potency is not indicated (e.g. GDNF is nm, and compounds are μm). RET selectivity was gauged by quantification of signaling in cells not expressing RET but expressing other RTKs (negative Akt/Erk activation is wanted). Culture of various cell types with the compounds in serum-containing media gauged general toxicity, and culture in serum-free conditions gauged accelerated or delayed cell death. The use of various cell types in such assays evaluated RET dependence. Q525 is highlighted as a potential lead with the best balance overall. +, low/poor; ++, moderate; +++, high; —, not tested/not applicable. The summary illustrates the interplay that exists between the different parameters and profiles and the challenges of choosing a lead agent.

Test	Potency	RET selectivity	GFRa1-dependent	Toxicity
GDNF	++++	+++	Yes	—
121	++	+	Yes	++
128	+	+	—	++
101	+	+	—	+++
105	++	+	No	+++
112	+++	+	No	+++
141	++	+	No	+++
143	+	—	—	+++
151	++	+	No	+++
1047	+++	+	No	+++
2003	+	+	—	+
2004	+	+	—	+
508	++	+++	No	+
525	+++	+++	No	+
1041	+	—	—	—
1048	+	—	—	—