1. Project Profile

(1) Asset type: Molecular Inhibitor

(2) Indications: Solid tumor ( NSCLC, Pancreatic Ductal Adenocarcinoma )

(3) Dosage form and administration: Oral, Once Daily

(4) Research phase: IND Enabling

(5) Cooperation demands: License-out

2.Strategy of Design

RAS proteins are small GTPases that drive cell proliferation and survival when bound to GTP.
Mutant RAS proteins exist predominantly in the GTP-bound (RAS(ON)) state, leading to excessive downstream signaling via interaction with effectors such as RAF.
Targeting the RAS(ON) state is believed to be critical for maximal suppression of oncogenic RAS.
Tri-Complex Enables Selective Targeting of RAS (ON) Proteins, blocking the binding between RAF and Tri-complex, thus inhibiting signal transport and tumor growth

Asset can enter a cell and reversibly bind to the abundant cellular chaperone, Cyclophilin A(CYPA, itself has no affinity for binding to RAS)
Asset remodels the surface of CYPA to form a binary-complex with a high affinity for the on form of RAS(ON).
The tri-Complex(RAS^on-Asset-CYPA) inactivates RAS signaling by sterically occluding RAS binding domain(RBD) binding and preventing activation of downstream RAS pathway-effective substance of proteins.
Thusly, the tumor growth is inhibited.

3. Highlights

Asset shows 3~4 timesthe antiproliferative potency than RMC-6236 in multiple RAS Mutant tumor cells.
Excellent PD profile:
Asset showed 10 x higherpotency than RMC-6236 in Capan-2 (KRAS^G12V) CDX Model, achieving tumor regression at 0.3 mg/kg.

Asset showed over 8 x higher potencythan RMC-6236 in KP-4 (KRAS^G12D) CDX Model.

Asset shows a favorable ADME and PK profile
Asset exhibited improved in vivo clearance and exposure as compared with RMC-6236.
Lower CL, longer T_1/2, Higher exposure and oral bioavailability (1.6x in dog) vs RMC-6236
Great Safety Profile: 10~20x window (GLP tox.)
Lower Predicted Effective Human Dose(<10 mg, QD) vs RMC6236(300mg, QD)