Glioblastoma: Current Status, Emerging Targets, and Recent Advances

Abstract

Glioblastoma (GBM) is a highly malignant brain tumor characterized by a heterogeneous population of genetically unstable and highly infiltrative cells that are resistant to chemotherapy. Although substantial efforts have been invested in the field of anti-GBM drug discovery in the past decade, success has primarily been confined to the preclinical level, and clinical studies have often been hampered due to efficacy-, selectivity-, or physicochemical property-related issues. Thus, expansion of the list of molecular targets coupled with a pragmatic design of new small-molecule inhibitors with central nervous system (CNS)-penetrating ability is required to steer the wheels of anti-GBM drug discovery endeavors. This Perspective presents various aspects of drug discovery (challenges in GBM drug discovery and delivery, therapeutic targets, and agents under clinical investigation). The comprehensively covered sections include the recent medicinal chemistry campaigns embarked upon to validate the potential of numerous enzymes/proteins/receptors as therapeutic targets in GBM.

Figure 1

(A) Mechanism of action of TMZ. (B) MGMT-mediated innate resistance to TMZ.

Figure 2

Selective class I phosphatidylinositol 3-kinases inhibitors.

Figure 3

Major metabolites of lead compound and identification of clinical candidate AMG 511.

Figure 4

PI3K inhibitors with improved blood–brain penetration for the treatment of GBM.

Figure 5

Aptamer-functionalized nanosystems for GBM.

Figure 6

(A) Structural modification of ZSTK474 as PI3K inhibitors. (B) 2-Amino-4-methylquinazoline derivatives as potential PI3K inhibitors.

Figure 7

FAK inhibitors as anti-tumor agents.

Figure 8

FAK inhibitors as potential anti-GBM agents.

Figure 9

DYRK as a target for the treatment of GBM.

Figure 10

Kinase inhibitors of various classes as potential anti-glioma agents.

Figure 11

HDAC inhibitors for the treatment of GBM.

Figure 12

New class III HDAC inhibitors for the treatment of glioma.

Figure 13

Bioorthogonal uncaging to enhance the pharmacokinetic properties of HDAC inhibitor.

Figure 14

(A) Sahaquine, (B) largazole, (C) peptoid-based histone deacetylase inhibitor, (D) 4-vinylbiphenyl skeleton as histone deacetylase inhibitor, and (E) JOC 1 as potential HDAC inhibitor.

Figure 15

IDH inhibitors.

Figure 16

2-Thiohydantoin derivative as IDH inhibitors.

Figure 17

Quinolinone-based P2X7 receptor antagonist as anti-GBM agents.

Figure 18

Structure optimization of potent IDH1 inhibitor FT-2102 (Olutasidenib).

Figure 19

SAR studies of 4-phenylquinazoline-2-carboxamides for TSPO activity.

Figure 20

Wild-type TSPO ligand.

Figure 21

4-Phenylquinazoline-based TSPO ligands.

Figure 22

TSPO ligand as potential anti-cancer agent against glioma.

Figure 23

Quinazoline-urea-based TSPO inhibitor against GBM.

Figure 24

PDI inhibitors for the treatment of GBM.

Figure 25

PDI inhibitors lead to optimization for glioma.

Figure 26

Indolyl propenones as putative anti-cancer drug against GBM.

Figure 27

Pyrrolo[2,3-d]pyrimidines as potent tubulin-targeting scaffolds.

Figure 28

Indole-based anti-cancer agents.

Figure 29

Photosensitive activation of microtubules destabilizing agent.

Figure 30

(A) Modified carbazoles as anti-GBM agents. (B) Pyrrole derivatives as tubulin targeting agents for GBM.

Figure 31

Microtubule disrupting agents for the treatment of glioma.

Figure 32

HIF pathway inhibitors as anti-cancer agents.

Figure 33

HIF-1 pathway inhibitors as anti-cancer agents.

Figure 34

RGD integrins and dual MDM inhibitors for the treatment of GBM.

Figure 35

MDM-2 and TSPO for the treatment of gliomas.

Figure 36

Combination of oxidosqualene cyclase inhibitors with Atorvastatin for the treatment of glioma.

Figure 37

(A) Corin as a potential anti-glioma agent. (B) Multi-targeting compounds 147 and 148.

Figure 38

Degraders as anti-GBM agents.

Figure 39

Natural-product-based anti-GBM agents.

Figure 40

Parthenolide dimer as pyruvate kinase M2 activator.

Figure 41

(A) Quinic acid derivatives-based anti-GBM agents. (B) Punicic acid. (C) Grincamycin-B.

Figure 42

Radiolabeled olaparib as bioimaging tool for glioma detection.

Figure 43

[¹¹C] MPC-6627 radio ligand for GBM imaging.

Figure 44

TSPO radiotracers for ischemic brain and glioma.

Figure 45

Carborane-containing boron dipyrromethenes (BODIPYs) as probes for the boron neutron capture therapy.

Figure 46

Cyanine–gemcitabine conjugates as targeted theranostic agents.

Figure 47

PLD targeting agents for the treatment of GBM.

Figure 48

Thyrointegrin α_vβ₃ atagonists as effective tools against GBM.

Figure 49

Nimesulide analouges as potential anti-GBM agents.

Figure 50

α7-nAChR and α9-nAChR antagonists for the treatment of glioma.

Figure 51

Oxaphosphinanes as anti-GBM agents.

Figure 52

Benzazole derivatives as potent anti-heparanase agents.

Figure 53

Non-cyclam tetraamines as CXCR4 inhibitors.

Figure 54

Aldehyde dehydrogenase inhibitors against GBM.

Figure 55

Adenosine A3 receptor antagonists against GBM.

Figure 56

Pyrazolo[3,4-d]pyrimidine as potent anti-GBM agent.

Figure 57

Identification of diazo-5-oxo-l-norleucine (DON) prodrugs for the treatment of GBM.

Figure 58

Vacquinol-1 stereoisomers for the treatment of glioma.

Figure 59

2-Aryl-2-(3-indolyl)acetohydroxamates active against MDR cancer cell line.

Figure 60

GULT inhibitors as anti-cancer agents.

Figure 61

Various chemical structures as potential anti-GBM agents.

Figure 62

Various scaffolds and polymers for the treatment of GBM.

Figure 63

Various scaffolds as potential anti-GBM agents.

Figure 64

EphA2 agonist as potential anti-GBM agents.

Figure 65

Anti-GBM agents.

Figure 66

Different approaches for drug delivery to brain.