Another "Holy Grail": A geo-specific esterase that cleaves the Arg-ester of ST2002 at position 3 or 9

Staurosporine (ST) is a highly cell permeable but non-specific kinase inhibitor. To make this compound highly specific for the oncogenic/ageing kinase PAK1, ST should bear a bulky side chain at position 3 or 9 to exclude all kinases except for PAK1. Furthermore, it has been known for more than a decade, OH at position 3 (or 9)=ST2001, but not both (ST2002), boosts the anti-PAK1 activity by 50 times (reaching IC50=1 nM). ST is not water-soluble, but if you attach the basic amino acids such as Arg and Lys, to position 3 or 9 (or both), it becomes water-soluble and more cell-permeable.  Considering these factors, we are currently designing a potent, water-soluble, highly cell-permeable PAK1-specific ST derivatives called "ST3009".

ST2001 was found in a marine organism more than a decade ago, but this organism has vanished from the ocean sadly.  Chemical synthesis of ST2001 is possible, but its yield is so low, and economically unfeasable. The major product of ST (chemical) hydroxylation is ST2002 in which both 3 and 9 is hydroxylated.  Unfortunately, ST2002 has no anti-PAK1 activity.

Thus, to make the ST3009 (golden egg) efficiently, we have to esterize ST2002 at both positions 3 and 9 chemically, making ST3003 first, and then cleave only one of these ester bonds geo-selectively by a specific esterase, eventually yielding the ST3009.  This sort of "geo-specific" esterase is our "Holy Grail" in the forthcoming ST3009 project.