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. Author manuscript; available in PMC: 2015 Mar 1.
Published in final edited form as: Future Oncol. 2014 May;10(7):1215–1237. doi: 10.2217/fon.14.60

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].