Small molecule inhibitors in pancreatic cancer

Abstract

Pancreatic cancer (PC), with a 5 year survival of <7%, is one of the most fatal of all human cancers. The highly aggressive and metastatic character of this disease poses a challenge that current therapies are failing, despite significant efforts, to meet. This review examines the current status of the 35 small molecule inhibitors targeting pancreatic cancer in clinical trials and the >50 currently under investigation. These compounds inhibit biological targets spanning protein kinases, STAT3, BET, HDACs and Bcl-2 family proteins. Unsurprisingly, protein kinase inhibitors are overrepresented. Some trials show promise; a phase I combination trial of vorinostat 11 and capecitabine 17 gave a median overall survival (MoS) of 13 months and a phase II study of pazopanib 15 showed a MoS of 25 months. The current standard of care for metastatic pancreatic ductal adenocarcinoma, fluorouracil/folic acid (5-FU, Adrucil®), and gemcitabine (GEMZAR®) afforded a MoS of 23 and 23.6 months (EPAC-3 study), respectively. In patients who can tolerate the FOLFIRINOX regime, this is becoming the standard of treatment with a MoS of 11.1 months. Clinical study progress has been slow with limited improvement in patient survival relative to gemcitabine 1 monotherapy. A major cause of low PC survival is the late stage of diagnosis, occurring in patients who consider typical early stage warning signs of aches and pains normal. The selection of patients with specific disease phenotypes, the use of improved efficient drug combinations, the identification of biomarkers to specific cancer subtypes and more effective designs of investigation have improved outcomes. To move beyond the current dire condition and paucity of PC treatment options, determination of the best regimes and new treatment options is a challenge that must be met. The reasons for poor PC prognosis have remained largely unchanged for 20 years. This is arguably a consequence of significant changes in the drug discovery landscape, and the increasing pressure on academia to deliver short term 'media' friendly short-term news 'bites'. PC research sits at a pivotal point. Perhaps the greatest challenge is enacting a culture change that recognises that major breakthroughs are a result of blue sky, truly innovative and curiosity driven research.

Fig. 1. Chemical structures of gemcitabine (1), 5-fluorouracil (5-FU; 2), paclitaxel (3), leucovorin (4), irinotecan (5) and oxaliplatin (6).

Fig. 2. Chemical structures of the small molecule inhibitors (7–16) of PC with positive outcomes in phase I clinical trials, and capecitabine (17). Of note, the vorinostat (13) and capecitabine (17) combination phase I clinical trial showed an encouraging MoS of 1.1 year.

Fig. 3. Chemical structures of the small molecule inhibitors pazopanib (18), vatalanib (19), galunisertib (20), hydroxychloroquine (21) and lapatinib (22) in phase II clinical trials targeting PC.

Fig. 4. Phase II pancreatic cancer clinical trial candidates that failed to show statistically significant improvements in MoS or failed at phase II for other reasons as either single agents or in combination with gemcitabine (1): vandetanib (23), sorafenib (24), erlotinib (25), dasatinib (26), saracatinib (27), imatinib (28) vismodegib (29), dactolisib (30), everolimus (31), PX-12 (32), veliparib (33), trametinib (34) and selumetinib (35). Note that erlotinib (25) in combination with gemcitabine (1) was approved for locally advanced, unresectable or metastatic PC in 2005.

Fig. 5. Chemical structures of rigosertib (36), olaparib (37), axitinib (38), cisplatin (39) and mitomycin C (40) that failed to meet the phase III PC endpoint or failed at phase II due to toxicity issues. Sunitinib (41) was approved to treat patients with progressive, well-differentiated pNETs in 2011.

Fig. 6. Chemical structures of small molecule inhibitors of protein kinases under investigation for their efficacy against pancreatic cancer: PD173074 (42), PKC412 (43), BGB324 (44), GSK2256098 (45), PF573228 (46), binimetinib (47) and cobimetinib (48).

Fig. 7. Chemical structures of small molecule inhibitors of protein kinase R-like endoplasmic reticulum kinase under investigation for their efficacy against pancreatic cancer: GSK2656157 (49), 3-(2,5-dimethoxyphenyl)-N-((4-(5-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-4-yl)pyridin-2-yl) carbamoyl)-propanamide (50), SCH727965 (51), and AZD6738 (52).

Fig. 8. Chemical structures of small molecule inhibitors of signal transducer and activator of transcription 3: L61H46 (53), PG-S3-001 (54), HJC0416 (55), XZH-5 (56), methyl N-(((3,5-bis(trifluoromethyl)phenyl)-carbamoyl)isoleucyl)-N^‘-methyl-l-histidinate (57) and cryptotanshinone (58).

Fig. 9. Chemical structures of small molecule inhibitors of bromodomain and extra-terminal proteins: JQ1 (59) and I-BET 762 (60).

Fig. 10. Chemical structures of small molecule inhibitors of histone deacetylases: ST3595 (61), CG200745 (62), mocetinostat (63), belinostat (64) and panobinostat (65).

Fig. 11. Chemical structures of small molecule inhibitors of Bcl-2 family proteins: UMI-77 (66), 4-((6-nitroquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide (67), 2,3,4,6-tetrahydroxy-5H-benzoannulen-5-one (68), TW-37 (69) and ABT737 (70).

Fig. 12. Chemical structures of small molecule inhibitors of other aberrant signalling pathways linked to pancreatic cancer: BMS-754807 (71), P1608K04 (72), MI-319 (73), NPC26 (74), spongiatriol (75) and SWIV-134 (76).

Fig. 13. Chemical structures of small molecule inhibitors of Bcl-2 family proteins: BAY ACC002 (77), ICG-001 (78), and IPI269609 (79).

Fig. 14. Chemical structures of miscellaneous inhibitors under preclinical evaluation for potential use in the treatment of PC: MRK-003 (80), MDC-1016 (81), and TIC10/ONC201 (82).

Jufeng Sun

Cecilia C Russell

Christopher Scarlett

Adam McCluskey