Small molecules targeting protein-protein interactions for cancer therapy

Abstract

Protein-protein interactions (PPIs) are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases. Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases, especially tumours. Encouragingly, selective PPI-based therapeutic agents have been rapidly advancing over the past decade, providing promising perspectives for novel therapies for patients with cancer. In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects, focusing on PPIs in disease, drug design and discovery strategies, structure-activity relationships, inherent dilemmas, and future directions.

Keywords: Cancer; Protein‒protein interactions; Small molecules; Structure-activity relationships.

Graphical abstract

Figure 1

Mechanisms for PPI modulators: allosteric and orthosteric.

Figure 2

Inhibitors of the Bcl protein family. (A) Two categories of the Bcl protein family: anti-apoptotic Bcl-2 proteins and pro-apoptotic Bcl-2 proteins. The proapoptotic Bcl-2 proteins have two categories: multi-BH proteins and BH3-only proteins. (B) Chemical structures of the Bcl-2 inhibitors. (C) Chemical structure of ABT-199 and its indicated binding mode. (D) The cocrystal structure of Bcl with ABT-199 (PDB: 6O0K). The protein is illustrated with surface atoms, and compound atoms are in different colours: C, green; N, blue; O, red; S, brown; Cl, pink.

Figure 3

Inhibitors of Bcl-XL. (A) Chemical structures of WEHI-539 and A-1155463. (B) Design of the inhibitor A-1293102: chemical structures of 6–8. (C) Chemical structure of A-1293102 and its indicated binding mode. (D) The cocrystal structure of Bcl with A-1293102 (PDB:7LH7). The protein is illustrated with white‒blue ribbons, and the hydrogen bonds are depicted in yellow dashed lines. Compound atoms are in different colours: C, green; N, blue; O, red; S, brown; F, warm pink.

Figure 4

Chemical structures of MCL-1 inhibitors. (A) Chemical structures of 9 and 10. (B) Chemical structures of 11‒14.

Figure 5

Inhibitors of XIAP. (A) Functional domains of XIAP, including three BIR domains, a UBA domain and a RING domain. (B) Chemical structures of inhibitors 15–20: AVPI-based Smac polypeptide mimics 15–17. (C) Conformation-constrained monovalent IAP antagonists18‒20.

Figure 6

Chemical structures of inhibitors 21–23: (A) Bivalent IAP inhibitor birinapant. (B) Nonalanine IAP antagonists 22 and 23. (C) Chemical structure of ASTX660 and its indicated binding mode. (D) The cocrystal structure of XIAP with ASTX660 (PDB: 5OQW). The protein is illustrated with white-blue ribbons, and the hydrogen bonds are depicted in yellow dashed lines. Compound atoms are in different colours: C, green; N, blue; O, red; F, warm pink.

Figure 7

Inhibitors of MDM2‒p53. (A) The complex of MDM2‒p53 (PDB: 1T4F). (B) MDM2‒p53 inhibitors 24–27: design of the inhibitor RG7112. (C) Chemical structure of RG7112 and its indicated binding mode. (D) The cocrystal structure of MDM2 with RG7112 (PDB:4IPF). The protein is illustrated with surface atoms. Compound atoms are in different colours: C, green; N, blue; O, red; S, brown; Cl, pink.

Figure 8

Design of the inhibitor RG7388. (A) Chemical structure of 28 and 29. (B) Chemical structure of 28 and its indicated binding mode. (C) The cocrystal structure of MDM2 with 28 (PDB:4JRG). The protein is illustrated with surface atoms. Compound atoms are in different colours: C, green; N, blue; O, red; CN, orange; Cl, pink.

Figure 9

CD40‒CD40L inhibitors. (A) The crystal structure of CD40‒CD40L. (PDB:3QD6). (B) Design of inhibitor DIR-C21045.

Figure 10

PD-1‒PDL1 inhibitors 35–46. (A) Chemical structure of 38‒40 produced by BMS Corporation. (B) Chemical structure of 41‒44. (C) Chemical structure of 1-caffeoylquinic acid. (D) Chemical structure of CA-170.

Figure 11

Structure of the complex of human programmed death-1 (PD-1) and its PD-L1 ligand (PDB: 4ZQK). There are three main hotspots: 1) Tyr56, Glu58, Arg113, Met115, and Tyr123; 2) Met115, Ala121, and Tyr123; and 3) the main and side chains form extension grooves, from Asp122 to Arg125, and the two sides are Asp26.

Figure 12

Chemical structure of inhibitors 47–54.

Figure 13

Inhibitors of C-Myc‒MAX. (A) Functional domain structure of the C-Myc protein. (B) Cocrystal structure of DNA-bound basic helix loop helix leucine zipper (bHLHZip) domains of C-Myc‒Max (PDB:1NKP). (C) Chemical structure of 55‒58.

Figure 14

Inhibitors of Menin‒MLL. (A) Chemical structures of KO-639 and SNDX-5613. (B) Design of the M-1121 inhibitor: chemical structure of 61‒64. (C) Chemical structure of M-1121 and its indicated binding mode. (D) The cocrystal structure of Menin with M-1121 (PDB:7M4T). The protein is illustrated with white‒blue ribbons, and the hydrogen bonds are depicted in yellow dashed lines. Compound atoms are in different colours: C, green; N, blue; O, red; S, orange; F, warm pink.

Figure 15

Design of the inhibitor KI-696. (A) Chemical structure of 66‒71. (B) Chemical structure of KI-696 and its indicated binding mode. (C) The cocrystal structure of Keap1 with KI-696 (PDB:5fnu). The protein is illustrated with white‒blue ribbons, and hydrogen bonds and π-stacking interactions are represented by yellow and red dashed lines, respectively. Compound atoms are in different colours: C, green; N, blue; O, red; S, orange.

Figure 16

Kras‒SOS1 inhibitors 72–75. (A) Chemical structures of BI-68BS and BI-3406. (B) Chemical structure of BAY-293 and the EGFR inhibitor erlotinib.

Figure 17

Design of the inhibitor MRTX0902. (A) Chemical structure of 76‒78. (B) Chemical structure of MRTX0902 and its indicated binding mode. (C) The cocrystal structure of SOS1 with MRTX0902 (PDB:7UKR). The protein is illustrated with white‒blue ribbons and the hydrogen bonds, the salt bridge and the π-stacking interaction are depicted in yellow, red and blue dashed lines, respectively. Compound atoms are in different colours: C, green; N, blue; O, red; CN, orange.

Figure 18

Chemical structure of inhibitors 79–85.

Figure 19

Microtubule stabilizers. (A) The crystal structure of αβ-microtubule (PDB:4FFB). (B) Chemical structures of paclitaxel. (C) Photolabelling sites on β-tubulin obtained with three analogues of paclitaxel. (D) Chemical structures of 87 and 88.