Platform

Rationally Designed to Maximize Patient Benefit

We’re overcoming the limitations of current RAS-targeted approaches, aiming to realize the full promise of KRAS and PI3K inhibition.

Program & Indication

Pre-Clinical Phase 1 Phase 2 Phase 3

BBO-8520

- Phase 1

A direct inhibitor targeting the “ON” and “OFF” states of KRAS. We are currently enrolling the ONKORAS-101 trial for patients with KRAS^G12C mutant non-small cell lung cancer (NSCLC).

ONKORAS-101 is an open-label, multi-center Phase 1a/1b study designed to evaluate the safety, tolerability, preliminary antitumor activity, and pharmacokinetics of BBO-8520 as a single agent and in combination with pembrolizumab in patients with KRAS^G12C mutant NSCLC.

BBO-10203

- Phase 1

A PI3Kα:RAS breaker designed to inhibit PI3Kα/AKT signaling in tumors while critically avoiding hyperglycemia. We anticipate patient enrollment later in the year.

BBO-11818

- Pre-Clinical

A pan-KRAS inhibitor targeting its “ON” and “OFF” states with high potency against both G12D and G12V mutants. We expect to file an IND in early 2025.

Why RAS?

RAS mutations drive more than 30% of all human cancers, including the most deadly types, by effecting aberrant RAS signaling that results in uncontrolled tumor growth.

In 2021, the FDA approved the first therapeutic targeting the KRAS^G12C mutation; a huge breakthrough for non-small cell lung cancer (NSCLC) patients. KRAS mutations appear in approximately 30% of NSCLC cases, 40% of colorectal cancer (CRC) cases, and 90% of pancreatic ductal adenocarcinomas (PDAC) cases.

However, current direct KRAS-targeted approaches exclusively target the “OFF” state of the protein, which has no biological function. These agents “lock” the mutant KRAS in the “OFF” state, limiting the amount of active “ON” KRAS^G12C available to signal. However, this approach has limitations, such as incomplete target inhibition. More importantly, the adaptive resistance that can arise through multiple cellular mechanisms increases the population of the oncogenic “ON” state. These adaptive mechanisms result in short duration of response and limited clinical benefit for patients.

Our approach to rational drug design is informed by RAS cancer biology, and is key to advancing new RAS-targeted approaches that could significantly improve patient outcomes.

What’s RAS?

The RAS gene family encodes proteins crucial in controlling cell proliferation, differentiation, and survival, which can lead to cancer. 

KRAS is a member of the RAS gene family and is one of the most commonly mutated genes in human solid tumors. A specific mutation in the KRAS gene, KRAS^G12C, results in a constantly active (“ON”) K-Ras protein that continuously activates downstream pathways, such as MAPK/ERK and PI3K/AKT, leading to uncontrolled cell growth and cancer progression. The “ON” form was once considered “undruggable,” but we now understand that targeting the “ON” state is possible and represents a clinically meaningful target that is distinct from the “OFF” state.

We aim to overcome the limitations of existing therapies by pursuing multiple approaches with drugs that target both the “ON” and “OFF” forms, including KRAS^G12C and pan-KRAS inhibitors.

Why PI3Kα?

The importance of PI3Kα in cancer has been demonstrated by first generation PI3Kα kinase inhibitors that provide clinical benefit to breast cancer patients. However, these agents are severely constrained by on-target toxicities that limit their effectiveness.

New research is elucidating how RAS activates the PI3Kα pathway, showing that it plays an important role in tumorigenesis but a limited role in normal physiology. This important dichotomy sets the stage for a new therapeutic approach: the potential to block the interaction between KRAS and PI3Kα and deliver more effective cancer therapies, providing physicians and patients with additional therapeutic options to expand treatment possibilities.

We are developing a therapeutic designed to break the cancer-causing interaction between RAS and PI3Kα that does not harm healthy cells, bypasses glucose metabolism signaling, and avoids hyperglycemia.