KRAS^G12D mutant cancers represent a significant unmet medical need with 55,000 new diagnoses annually in the US largely in colorectal, pancreatic, and non-small cell lung cancers. RMC-9805, a potent, selective, orally bioavailable, covalent KRAS^G12D(ON) inhibitor, produced deep, durable suppression of tumor KRAS pathway activation in vivo following repeat oral administration. Profound tumor regressions were observed in KRAS^G12D mutant xenograft models in mice and all dose regimens were well tolerated.

Knowledge and structure-based design approaches derived a diverse series of covalent inhibitors that selectively target KRASG12C. Key to developing these compounds has been unique structural and conformational insights, identifying and overcoming cross-species PK differences, and solving significant synthetic challenges at scale. This talk will highlight our development of candidate drug AZD4625, a highly potent and selective inhibitor of KRASG12C with anticipated low clearance and high oral bioavailability profile in humans.

Mutations in KRAS are common oncogenic drivers. GDC-6036 is an orally bioavailable, highly potent and selective KRAS G12C inhibitor. GDC-6036 demonstrates greater potency and selectivity compared with other KRAS G12C inhibitors in vitro, and complete tumor growth inhibition in multiple KRAS G12C-positive cell lines and in xenograft mouse models. We will present the research program that led to the discovery and optimization of GDC-6036, which is currently in clinical development.

KRAS mutations are frequent driver mutations in human cancers. The guanine nucleotide exchange factor, SOS1, regulates the shift of KRAS from the GDP-loaded “off” state to its GTP-loaded “on” state. MRTX0902 is a potent, selective, brain penetrant, and orally bioavailable inhibitor of the SOS1:KRASG12C protein-protein interaction that causes tumor regressions when dosed with our KRASG12C inhibitor adagrasib in several preclinical models. The discovery and characterization of MRTX0902 will be presented.

KRASG12C inhibitors deliver clinical benefit, most patients who achieved an objective response ultimately progressed. Multiple ongoing trials seek to augment responses to KRASG12C inhibitors through rational combination strategies, including the first-in-class pan-KRAS SOS1 inhibitor BI 1701963. Here we use different preclinical experimental approaches to interrogate KRASG12C inhibitor resistance mechanisms with the aim to identify strategies to overcome resistance. I will present: KRASG12C inhibitors deliver clinical benefit; combination strategies with first-in-class pan-KRAS SOS1 inhibitor BI 1701963; and identify strategies to overcome KRASG12C inhibitor resistance.

The discovery of covalent inhibitors of KRASG12C has reinvigorated the field of KRAS drug discovery. While these compounds have shown promising clinic results, we wanted to explore PROTAC-mediated degradation as a complementary strategy to modulate KRASG12C.  We report the development of LC-2, the first PROTAC capable of degrading endogenous KRASG12C.  LC-2 induces rapid, sustained KRASG12C degradation and suppresses MAPK signaling. LC-2 demonstrates that PROTAC-mediated degradation can attenuate oncogenic KRAS levels.

RAS proteins in the mitogen-activated protein kinase (MAPK) signaling pathway are the most frequently mutated oncogenes in cancer. Recent studies have shown that RAS expressed and purified from E. coli copurifies with different forms on guanosine nucleotides, including the 2’-deoxy form. Here, we use native mass spectrometry to study the biochemical properties of RAS bound to various nucleotides along with the molecular complexes they form with the guanine nucleotide exchange factor Son of Sevenless. We also find the intrinsic GTPase activity of oncogenic RAS mutants is dependent on the form of guanosine triphosphate.

Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and therapeutic window for the treatment of cancer.  Despite the success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS have not been developed.  In this talk, I will discuss the discovery of agents that selectively target KRAS mutants beyond G12C, including small molecules that covalently reacts with KRAS G12S and KRAS G12R.

The Synthetic lethality strategy has become a very attractive approach for “non-druggable” genes, such as KRAS and cMyc, in cancer treatments. We developed a new quantitative FRET (qFRET)-based HTS to discover a novel SUMOylation inhibitor that shows potent cell death-inducing activities with KRAS mutations at G12 or Q61 in cells and xenograft model. The SUMOylation inhibitor can serve as a chemical tool as well as a lead compound to test the new strategy for cancers, in which tumorigenesis is induced by those difficult-to-be targeted genes using other approaches.

FDA approval of the first KRAS inhibitor has rejuvenated the field, however, drugging other KRAS mutants remains a challenge. We will describe Conformation Locking Antibodies for Molecular Probe discovery (CLAMPs) that recognize and induce a rare KRAS conformation. We will describe broad application of CLAMPs to detect inhibitor-bound KRAS in cells and tumors, serve as a structural chaperone, and enable a high-throughput screen to discover small-molecule ligands.

The Ral-GEF pathway is one of the three major K-RAS signaling pathways. Ral GTPases are difficult targets, but Rgl2, a Ral guanine exchange factor, has several cysteines on its surface.  We screened a library of cysteine electrophiles and identified fragments that inhibited Ral GTPase exchange by Rgl2. These allosteric covalent fragment inhibitors provide a starting point for the development of small-molecule covalent inhibitors to inhibit RAS signaling in animal models.

The cellular activity of Ras is modulated by its association with the guanine nucleotide exchange factor Sos, and the high-resolution crystal structure of the Ras–Sos complex provides a basis for the rational design of orthosteric Ras ligands. We constructed a synthetic Sos mimic that engages the wild-type and oncogenic forms of nucleotide-bound Ras and modulates downstream kinase signaling. Chemoproteomic studies illustrate that the proteomimetic engages Ras and other cellular GTPases. The proteomimetic resists proteolytic degradation and enters cells through macropinocytosis. As such, it is selectively toxic to cancer cells with up-regulated macropinocytosis, including those that feature oncogenic Ras mutations.