Kit S Lam

Division of Hematology and Oncology, UCDMC

After the initial report of one-bead one-compound (OBOC) combinatorial library method in 1991 [1], we have made several improvements to the technology. These include the development of (i) topographically segregated bilayer beads such that the library compounds are on the outer layer of the bead and the encoding tags reside in the bead interior, (ii) chemical encoding methods using such bilayer beads for the synthesis of small molecule and peptidomimetic OBOC libraries [2],

(iii) high stringency screening methods for identification of high affinity ligands against soluble proteins and cell surface receptors, and (iv) peptide, small molecule and macrocyclic natural-product like libraries using the OBOC format. Through applying these various techniques, we were able to identify high affinity ligands that bind to specific cell surface receptors of living cells. For example, we have developed a peptidomimetic ligand LLP2A (IC_50 =2pM) that binds to activated a4b1 integrin of lymphoid cancers [3]. Using this ligand as a delivery vehicle, we have developed highly sensitive and specific /in vivo/ imaging and therapeutic agents for lymphoma. We have also identified unique ligands that bind to a4b1 integrin of ovarian cancer and glioblastoma, and successfully used these ligands as /in vivo/ optical and positron emission tomography (PET) imaging probes.

[1] Lam KS, Salmon SE, Hersh EM, Hruby V, Kazmierski WM, Knapp RJ.

Nature 354(7):82-84, 1991. [2] Liu R, Wang X, Song A, Bao T, Lam KS.

QSAR Combi. Sci., 24:1127-1140, 2005. [3] Peng L, Liu R, Marik J, Wang X, Takada Y, Lam KS. Nature Chemical Biology, 2(7). 381-389, 2006.