Modifying the chemistry of injection water yields improved wettability behavior on carbonate rock surfaces. Previous work has focused on demonstrating the effect of modified brine formulation on particular carbonate samples. Here the results of a more general screening study consisting of Amott spontaneous imbibition experiments on the samples from oil-bearing zones and from outcrops of different carbonate formations are reported. Tertiary incremental oil production due to increased water-wetness was observed upon transition to brine of lower ionic strength. Additional oil recovery from the spontaneous imbibition tests ranged from 4 to 20% of OIIP (Oil Initially In Place), reflecting a large variability in the response and indicating a high complexity of the mechanism(s). Consistent with numerous published reports, Stevns Klint outcrop chalk samples were a clear exception and exhibited increased oil recovery with increasing sulfate ion concentration. These did not respond to lowering the salinity of the imbibing brine. Tertiary oil recovery from samples containing evaporites occurred simultaneously with dissolution of salt minerals, as evident from brine analysis. However, incremental oil recovery in the same range was measured for samples without evaporites but from the same geological formation. Hence, mineral dissolution as a mechanism for enhanced oil recovery could not be confirmed. The results show that injection of low salinity brine into carbonate reservoirs has potential as an EOR technology. However, additional research is needed to improve the understanding of the underlying chemical and physical mechanisms and improve a priori predictability.

SummaryBRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.

BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.