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Efforts to Develop KRAS Inhibitors Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Efforts to Develop KRAS Inhibitors Matthew Holderfield NCI-Ras Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland 21702 Correspondence: [email protected] The high prevalence of KRAS mutations in human cancers and the lack of effective treatments for patients ranks KRAS among the most highly sought-after targets for preclinical oncologists. Pharmaceutical companies and academic laboratories have tried for decades to identify small molecule inhibitors of oncogenic KRAS proteins, but little progress has been made and many have labeled KRAS undruggable. However, recent progress in in silico screening, fragment- based drug design, disulfide tethered screening, and some emerging themes in RAS biology have caused the field to reconsider previously held notions about targeting KRAS. This review will cover some of the historical efforts to identify RAS inhibitors, and some of the most promising efforts currently being pursued. he age of whole-genome sequencing has late 1970s. First, DNAs from viruses and later Tpaved the road for “personalized” medicine from human tumor cells were shown to be suffi- in oncology. The Cancer Genome Atlas Re- cient totransform NIH-3T3 cellsin culture (Shih search Network (2017), the Cancer Cell Line et al. 1979; Shih et al. 1981). It was not until the Encyclopedia (Barretina et al. 2012), the Geno- early 1980s that KRAS was identified as the caus- mics of Drug Sensitivity in Cancer (Yang et al. ative oncogene (Der et al. 1982; Parada and 2013), and similar efforts aim to catalog driver Weinberg 1983). By 1987, KRAS oncogenes mutations with actionable and effective treat- were cloned from multiple tumor biopsies of ment regimens. While significant progress has lung, colon, and pancreas cancers (Santos et al. been made in some notable areas, including 1984; Bos et al. 1987; Forrester et al. 1987; Ro- www.perspectivesinmedicine.org BRAF-mutated melanomas (Davies et al. 2002; denhuis et al. 1987; Almoguera et al. 1988). By Chapman et al. 2011) and BRCA-mutated this time, all three RAS isoforms, H-, N-, and K- breast and ovarian cancers (Fong et al. 2009; RAS wereknown andmutations atcodons 12,13, The Cancer Genome Atlas Research Network and 61 of a RAS isoform were shown to be suffi- 2011), many of the most common oncogenes cienttoinducecell-cycleprogression.Finally,the were identified decades ago and remain the HRAS crystal structure revealed that the cancer- most deadly and elusive oncology drug targets. associated mutations at codons G12, G13, and Perhaps chief among these is KRAS. Q61 are each located at a site of guanosine tri- Interest in KRAS as a cancer target stems phosphate (GTP) binding, suggesting acommon from work with rodent sarcoma viruses in the mechanism of oncogenesis (Pai et al. 1989). Editors: Linda VanAelst, Julian Downward, and Frank McCormick Additional Perspectives on Ras and Cancer in the 21st Century available at www.perspectivesinmedicine.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a031864 Cite this article as Cold Spring Harb Perspect Med 2018;8:a031864 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press M. Holderfield It was later determined that RAS proteins strates, ERK1/ERK2 (Blasco et al. 2011). Like- are prenylated small GTPases. H-, N-, and K- wise, KRAS activation of PI3K is also essential in RAS are all farnesylated at the carboxyl termi- a similar NSCLC mouse model (Castellano et al. nus. H- and N-RAS as well as one of the two 2013). Unfortunately, KRAS-mutated cancers KRAS splice variants (KRAS 4A) are also palmi- and many of the available cell lines have proven toylated, whereas KRAS 4B contains a series of unresponsive to MEK, RAF, or PI3K inhibitors charged lysine residues near the carboxyl termi- administered as single agents (Barretina et al. nus that aid in membrane localization (Hancock 2012). Therefore, cotargeting the MAPK and 2003). Fully processed RAS proteins localize to PI3K pathways may be required to treat KRAS- the plasma membrane where they are activated driven cancers (Engelman et al. 2008). Unfortu- upon growth factor stimulus. Guanosine ex- nately, coadministration of PI3K and MEK in- change factors (GEFs) promote RAS–GTP asso- hibitors is not well tolerated. Phase I clinical ciation to offset the high rate of GTP hydrolysis trials reported grade 3 and 4 dose-limiting tox- in cells. Hydrolysis is stimulated by GTPase-ac- icities, which is thought to limit clinical efficacy tivating proteins (GAPs) (Trahey and McCor- (Bedard et al. 2015). Unless dosing regimens can mick 1987). Among the most well-characterized be modified to reduce general toxicity, cotarget- RAS GAP proteins are p120 and NF1, which ing MAPK and PI3K does not appear to be a increase GTP hydrolysis >10,000-fold over the viable therapeutic option, which further illus- intrinsic rate. GAP proteins all contain a cata- trates the unmet clinical need for effective treat- lytic arginine residue that fits into the active site ment strategies for KRAS-mutated cancers. This of RAS to stimulate hydrolysis of the terminal has, in part, nucleated a resurgence for basic GTP phosphate. Mutations at RAS G12, G13, or science and drug discovery efforts to target Q61 prevent the GAP arginine from accessing oncogenic KRAS proteins and to identify new GTP, which stabilizes RAS in the GTP-bound targets required for KRAS-driven oncogenesis. state (Scheffzek et al. 1997). In the GTP-bound form, RAS proteins asso- DIRECT TARGETING OF KRAS PROTEINS ciate with and activate a variety of effector mol- ecules including phosphatidylinositol-3 kinase The difficulties drugging RAS stem from the (PI3K) and the RAF kinases. RAF kinases ac- small size of the protein, just 21 kD, with a tivate the mitogen-activated protein kinase lack of an apparent “pocket” for a small mole- (MAPK) pathway by phosphorylating MEK1 cule to bind apart from the nucleotide substrate- and MEK2, which in turn phosphorylate ERK1 binding site. However, the high picomolar affin- and ERK2, which phosphorylate and activate ity reported for nucleotide substrates paired www.perspectivesinmedicine.org many transcription factors that promote cell- with the high millimolar cellular concentration cycle progression. Alternatively, PI3K activates of GTP suggests that this strategy is thermody- AKT and mechanistic target of rapamycin namically and pharmacologically unattainable. (mTOR) signaling to promote protein transla- As such, RAS proteins are commonly referred to tion. Unlike RAF kinases, PI3K can be activated as “undruggable,” but a renewed interest in tar- independent of RAS by receptor tyrosine kinases geting KRAS may change this paradigm (Ste- (RTKs) or indirectly through G-protein-cou- phen et al. 2014). This review will focus on pled receptor (GPCR) and integrin signaling, many of the strategies to target KRAS in the but both effector pathways are strongly impli- past, as well as some promising efforts that are cated in cancer progression and have been eval- currently being pursued. uated as therapeutic targets for KRAS-mutated cancers. Genetically engineered mouse models Targeting Nucleotide Exchange demonstrate that KRAS G12D-driven non- small-cell lung cancer (NSCLC) requires a single SCH54292 was described in the first report of a RAS isoform, CRAF, as well as the RAF client small molecule that binds directly to RAS (Ta- proteins, MEK1/MEK2, and the MEK sub- veras et al. 1997). The series was developed from 2 Cite this article as Cold Spring Harb Perspect Med 2018;8:a031864 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Efforts to Develop KRAS Inhibitors a biochemical screen designed to identify inhib- which makes inhibition thermodynamically un- itors of nucleotide exchange, and nuclear mag- favorable with a small molecule. However, a sin- netic resonance (NMR) studies showed that it gle-point mutation in the RAS-binding domain interacts with the Switch II domain of RAS in of RAF kinase or RAL-GDS is sufficient to abol- the guanosine diphosphate (GDP)-bound con- ish RAS-RAF or RAS-RAL-GDS binding (Fabi- formation. Similar studies have since been per- an et al. 1994), suggesting that even a minor formed by other groups using different nucleo- disruption of the RAS-effector binding site may tide exchange assays, but all nucleotide exchange prevent binding. Thus, assays that measure inhibitors typically suffer from low affinity for KRAS–effector interactions in vitro and in cell RAS (Cox et al. 2014) and often lack activity in systems have been used to screen many com- cells. None of the compounds identified have pound libraries. One such compound, MCP1, been developed for clinical use. was identified in an HRAS-CRAF yeast two-hy- More recently, three groups have used NMR brid screen, and demonstrated activity in NRAS- to identify small molecule fragments that bind to mutated HT1080, KRAS-mutated PANC-1, and RAS (Maurer et al. 2012; Sun et al. 2014; Winter A549 cells in the 10- to 20-µM range, but no et al. 2015). This strategy seeks to identify novel inhibition of BRAF V600E-mutated A2058 cells compound-binding pockets using low molecu- was observed (Kato-Stankiewicz et al. 2002). It is lar weight chemical matter and to improve af- not clear whether MCP1 binds directly to RAS finity by increasing the inhibitor size through a or CRAF, and the compound series is not potent rational structure-based drug design or by enough for therapeutic activity. However, the chemically linking multiple fragments with proposed mechanism of action remains a viable low affinity for the target protein. Many of the approach for inhibiting oncogenic KRAS signal chemical fragments identified bind to RAS in a transduction.
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