A single drug that can be used to treat multiple cancer types will significantly impact the clinical treatment system, as current drugs are restricted for a particular cancer type or sub type or even for some patients. This is economically untenable. Due to the complexity of cancers, currently the clinicians have to personalized medications with a huge cost, still with unexpected failures. Our approach is to develop a single drug that has efficacy in wider range of patients having different cancer types. This is clearly one of the major unmet needs in oncology drug discovery research and in the clinic. Such drugs will have a much greater market and will greatly reduce per-patient cancer care cost in the US and world-wide. KRAS, is one of the best-known key oncogenes in cancers with high mutation rates and is commonly expressed in many cancer types. However, some characteristics, including lack of classical well defined binding pocket for KRAS make it one of the most hard-to-hit targets in cancer research leading to dub KRAS as “undruggable” over 40 years. Only recently two KRAS inhibitors have been approved by FDA, still leaving great demand for novel and economical drugs with different mechanism of actions. With a clear understanding of why previous attempts have failed, we designed and developed a unique spider-like 3-dimentional (3D) peptoid drug-lead that can efficiently cover this unique binding surface with high cell permeability. We applied on-bead high throughput peptoid screening targeting mutated KRASG12V to identify this 3D peptoid drug-lead we called PKR1. We confirmed that the PKR1 binds to KRASG12V with Kd of 573 nM. Furthermore, we identified the minimum pharmacophore of PKR1. Since the membrane bound KRAS display different orientations in active states, we also added short fatty acid chain to PKR1 to anchor our peptoid to the membrane, applying a new approach to target mutant KRAS. The fatty acid conjugated peptoids indeed improved the activity over 25-fold, detected in the cellular cytotoxicity MTS assays. Further optimization of the membrane bound PKR1, the linkers, and the fatty acids are currently underway applying molecular docking studies. Overall, we have developed a membrane anchored 3D-peptoid as a novel drug candidate for difficult target KRAS protein, representing a novel mechanism of action in KRAS drug discovery arena. Success will also highlight a major conceptual paradigm shift in how we could practice drug development research, as this will open up other over-looked and/or abandoned ubiquitously expressing proteins for exploration as druggable targets using unique and specialized molecular classes such as peptoids.