Strategic Design of Catalytic Lysine‐Targeting Reversible Covalent BCR‐ABL Inhibitors**

Abstract

Supporting information for this article is given via a link at the end of the document.

Cell‐Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR‐ABL Kinase

“…Our examples herein show that targeting the catalytic lysine in protein kinases might hold an advantage in this context. Nonetheless, the mostly similar inhibition profiles between A5 / A11 and PPY‐A against various ABL mutants suggest that the degree of compound selectivity in A5 / A11 , which contained only moderately reactive warheads, [30] largely depended on the initial step of non‐covalent binding. FLT3, a kinase homologous to ABL and previously shown to be cross‐inhibited by PPY‐A, [31] was also potently inhibited by A5 (IC 50 =3.25 nM; Figure S2).…”

“…Further evidence of this covalent reversibility was obtained by using 1 H NMR upon dilution with a model complex between 2‐hydroxy‐benzaldehyde and Ac‐Lys‐NHMe (Figure S5) [44] . Further SAR analysis between A5 and A6 indicated that the presence of both OH/CHO and their precise positions were essential for covalent target engagement which was further stabilized by intramolecular H‐bond [30, 44] . By contrast, the Schiff‐base linkage formed between other analogs (such as A8 ) and K271 would be rapidly reversed by hydrolysis.…”

“…A total of 13 potential ABL inhibitors ( A1 – A13 ) were synthesized in order to establish SAR (Schemes 1/S1/S2 and Table 1). [30, 40] For selected inhibitors, the corresponding terminal alkyne‐containing activity‐based probes (ABPs), named ABP3 , ABP4 , ABP5 , ABP10 and ABP11 , were synthesized to further evaluate cell‐based covalent target engagement and potential off‐targets (Figures 2 and 3). [41–43] As shown in Table 1 and Figure 2A/B/C, the OPA‐containing A1 possessed potent in vitro inhibitory activity, thus confirming that R 1 /R 2 positions were tolerable to chemical modifications.…”

“…Despite attractive properties for functionalization of drugs and drug‐like molecules, [22] Ar‐OSO 2 F has not been exploited in the design of potential (latent) covalent lysine‐targeting kinase inhibitors [29] . We previously reported the first example of lysine‐targeting reversible covalent kinase inhibitor based on o ‐boronic acid benzaldehyde [30] . It had potent in vitro kinase inhibitory property but possessed poor/no cellular activities.…”

“… A) A general strategy to develop selective, irreversible and reversible covalent ABL inhibitors. B) Cocrystal structures of the ABL kinase domain with compound 14 (right; PDB ID: 7DT2) [30] . A “close‐up” view of R 1 /R 2 region indicates that this part was close to catalytic K271 in ABL kinase and had sufficient rooms to introduce different R 1 /R 2 groups.…”