Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology

Abstract

Controlling which particular members of a large protein family are targeted by a drug is key to achieving a desired therapeutic response. In this study, we report a rational data-driven strategy for achieving restricted polypharmacology in the design of antitumor agents selectively targeting the TYRO3, AXL, and MERTK (TAM) family tyrosine kinases. Our computational approach, based on the concept of fragments in structural environments (FRASE), distills relevant chemical information from structural and chemogenomic databases to assemble a three-dimensional inhibitor structure directly in the protein pocket. Target engagement by the inhibitors designed led to disruption of oncogenic phenotypes as demonstrated in enzymatic assays and in a panel of cancer cell lines, including acute lymphoblastic and myeloid leukemia (ALL/AML) and nonsmall cell lung cancer (NSCLC). Structural rationale underlying the approach was corroborated by X-ray crystallography. The lead compound demonstrated potent target inhibition in a pharmacodynamic study in leukemic mice.

Advances in Computational Polypharmacology

“…Going beyond standard scaffold‐ or pharmacophore‐based design, novel computational strategies for MT‐CPD design are developed. For example, to generate new inhibitors of the TAM (TYRO‐3, AXL, MERTK) family of receptor tyrosine kinases, which are implicated in immunosuppressive activity in tumor cells, kinase inhibitors from X‐ray structures were systematically fragmented, recording rings, functional groups, and interacting amino acids [23] . Starting from a known inhibitor available in an X‐ray complex with MERTK, stored fragments and corresponding amino acids were mapped onto the structure, retaining only those with interacting residues from the TAM family.…”

Enhancing Chemogenomics with Predictive Pharmacology

“…In this sense, structure-based approaches may be argued to offer another strategy for overcoming a lack of chemotype diversity among a set of known ligands. With the steady increase in structures in the Protein Data Bank as well as the availability of more powerful computers and cloud-based services to decrease calculation times, 3D and structure-based methods should become more attractive as a complement to 2D approaches …”

“…With the steady increase in structures in the Protein Data Bank 76 as well as the availability of more powerful computers and cloud-based services to decrease calculation times, 3D and structure-based methods should become more attractive as a complement to 2D approaches. 77 Of the headline criteria typically used to assess chemical probes (on-target activity, selectivity, and cellular penetration and distribution) the least attention, certainly in terms of the published scoring schemes, is paid to the third component. For targets that are embedded in the outer membrane of the cell and where the binding site is accessed from the extracellular side, provided that the probe compound is sufficiently soluble in the assay medium that may be sufficient to exert the expected pharmacological effect.…”

Organocatalytic asymmetric azidation of sulfoxonium ylides: mild synthesis of enantioenriched α-azido ketones bearing a labile tertiary stereocenter

“…4,5 As a result, a wide range of racemic or achiral methods have been developed for their synthesis. 1,6–12 However, their asymmetric synthesis remains a challenge. Among the few methods, catalytic asymmetric α -azidation of carbonyl compounds represents an attractive one, but it was implemented with only limited success (Scheme 1b).…”

“…To the best of our knowledge, catalytic asymmetric α -azidation of carbonyl compounds to generate a tertiary stereocenter remains unknown, 11 with the exception of a few multi-step approaches from enantioenriched precursors. 12 Adjacent to both carbonyl and azide functionalities, this type of doubly activated tertiary stereocenters are very labile (easy to racemize) and vulnerable to many reaction conditions. Moreover, chemoselectivity issues resulting from this tertiary center ( e.g.…”