Table 6.

Homologous recombination small-molecule inhibitors in development.

HR protein	Function(s)	Rationales for inhibiting	Challenges	Compounds being investigated
Rad51	Catalyzes the homology search Initiates DNA strand invasion and DNA strand exchange	The heart of HR activity	Incomplete characterization of Rad51's structure Determining whether direct or indirect inhibition would be more effective Unknowns regarding its activity (e.g., what triggers its nuclear translocation)	Cell studies only:
				• RI-1
RPA	Damage sensor, stabilizer Recruitment site for proteins involved in DNA replication, repair, recombination, and checkpoint activation	Essential for HR to happen	Common cleft/binding site for many proteins; difficult to isolate what would inhibit just DNA repair	Purified protein studies only:
				• Compound 4
Proteins that inhibit HR activity indirectly †
cAbl	Appears to be a decision maker, determining if damage is too extensive to be repaired	Inhibits Rad51's DNA strand exchange activity, which stalls HR Is activated by IR and alkylating agents A deletion or translocation on the gene promotes tumorigenesis cAbl-deficient cells are resistant to IR and other DNA-damaging agents	Participates in many cellular processes Inhibitors of cAbl also inhibit cKIT and possibly other tyrosine kinases; not specific to HR Also interacts with DNA-PK (in NHEJ pathway)	In clinical use:
				• Imatinib (Gleevec); available to treat CML since 2001; in trials for treating other cancers
				• Dasatinib
				• Nilotinib (Tasigna)
				• Bosutinib
PARP1	Surveillance/damage sensor Assesses extent of damage; determines whether to signal apoptosis Helps decondense chromatin Recruits repair proteins to the damage site Facilitates repairs	Uses NAD+ to transfer ADP-ribose polymers onto specific acceptor proteins including itself; this modifies the protein's properties PARP1 inhibition causes accumulation of DNA damage that collapses replication forks; cancers deficient in HR cannot repair such damage Inhibitors potentiate the effects of aklylating agents, platinating agents, topoisomerase 1 poisons, IR	Secondary mutations can correct for this repair deficiency, causing a resistance to PARPis	PARPis are available to treat familial breast cancers and other BRCA-like cancers >110 clinical trials in progress for second- and third-generation PARPis and broader use of first-generation inhibitors
HSP90	Facilitates the correct folding, maturing and stabilizing of many proteins into their active form	Protects cells under stress conditions; upregulated in cancers Inhibition triggers ubiquitination Inhibition disrupts multiple pathways: blocks all major hallmarks of cancer; triggers ubiquitination; decreases Rad51 levels, thwarting HR	Difficult to produce Inhibitory activity still being characterized; may inhibit one or more checkpoint kinases	In Phase I and II trials:
				• 17-DMAG
				• Alvespimycin (KOS-1022)
				• AT13387
				• AUY922
				• CNF2024 (BIIB021)
				• Debio 0932 (CUDC-305)
				• DS-2248
				• Ganetespib (STA-9090)
				• KW-2478
				• MPC-3100
				• PU-H71
				• Retaspimycin (IPI-504)
				• SNX-5422
				• XL-888
				In Phase III trials:
				• Tanespimycin (KOS-953; 17-AAG)
				Other candidates are in preclinical studies

Data on all PARP and HSP90 inhibitors in clinical trials are from [11].

^†No direct inhibitors of HR proteins have been found/developed yet. The proteins in this section inhibit HR activity indirectly by modulating DNAdamage response mechanisms, protein-protein interactions or other mechanisms.

CML: Chronic myelogenous leukemia; HR: Homologous recombination; IR: Ionizing radiation; NHEJ: Nonhomologous end joining.

Adapted with permission from [28].