The Evaluation of l‐Tryptophan Derivatives as Inhibitors of the l‐Type Amino Acid Transporter LAT1 (SLC7A5)

Abstract

A series of derivatives of the substrate amino acid l-tryptophan have been investigated for inhibition of the L-type amino acid transporter LAT1 (SLC7A5), which is an emerging target in anticancer drug discovery. Of the four isomeric 4-, 5-, 6-, or 7benzyloxy-l-tryptophans, the 5-substituted derivative was the most potent, with an IC 50 of 19 μM for inhibition of [ 3 H]-lleucine uptake into HT-29 human colon carcinoma cells. The replacement of the carboxy group in 5-benzyloxy-l-tryptophan by a bioisosteric tetrazole moiety led to a complete loss in potency. Likewise, the corresponding tetrazolide derived from l-tryptophan itself was found to be neither a substrate nor an inhibitor of the transporter. Increasing the steric bulk at the 5position, while reasonably well tolerated in some cases, did not result in an improvement in potency. At the same time, none of these derivatives was found to be a substrate for LAT1mediated transport.

Discovery of Antitrypanosomal Indolylacetamides by a Deconstruction–Optimization Strategy Applied to Paullones

“…The resulting acids 3 a – d were coupled with amines to yield the final products or Boc‐protected precursors ( 4 a – g , 5 a – e , g – k , 6 a – c , g , 7 a – d ). Because deprotection in diethyl ether yielded oily products, Boc‐protected compounds ( 4 b – d , g , 6 a – c ) were deprotected with hydrogen chloride in cyclopentyl methyl ether to yield the corresponding amino hydrochlorides ( 4 i – l , 6 d – f ) [22] . The methyl ether of 5 c was cleaved with boron tribromide in dichloromethane to give the phenol 5 f .…”

“…For products 4-7 the synthetic routes started from appropriately substituted ( 1 a,c-d 6 d-f). [22] The methyl ether of 5 c was cleaved with boron tribromide in dichloromethane to give the phenol 5 f.…”

Exploring Amino Acid Transporters as Therapeutic Targets for Cancer: An Examination of Inhibitor Structures, Selectivity Issues, and Discovery Approaches

“…Later, a tryptophan benzyloxy derivative (Compound 42 , Figure 3 ) was discovered as a LAT1 inhibitor (IC 50 = 1.48 µM) as part of a virtual screen implementing both structure-based and pharmacophore approaches [ 135 ]. This hit was then later used as a scaffold but did not allow the discovery of significantly more potent LAT1 inhibitors [ 136 ].…”

Divergent metabolomic signatures by LAT1 and LAT2 amino acid transporters and characterization of biased LAT1 inhibitors and mutations

“…Another LAT1 negative allosteric modulator, OKY-0434, is in Phase I/IIa clinical evaluation for patients with advanced pancreatic cancer (UMIN000036395 -Phase I/IIa Trial of R-OKY-034F for Pancreatic Cancer Patients, 2021). Other LAT1 inhibitors have been reported from academic drug discovery initiatives, including our own efforts in the NCCR TransCure (2010-2022) (Graff et al, 2022;K. M. Huttunen et al, 2016;Jeckelmann et al, 2022;Singh et al, 2019;Yan et al, 2021).…”